AREDIA

Main information

  • Trade name:
  • AREDIA Pdr/Conc/Soln for Infus 90 Anhyd Milligrams
  • Dosage:
  • 90 Anhyd Milligrams
  • Pharmaceutical form:
  • Pdr/Conc/Soln for Infus
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • AREDIA Pdr/Conc/Soln for Infus 90 Anhyd Milligrams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0013/090/004
  • Authorization date:
  • 05-07-1995
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PA0013/090/004

CaseNo:2081182

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

NovartisPharmaceuticalsUKLtd

FrimleyBusinessPark,Frimley,Camberley,Surrey,GU167SR,UnitedKingdom

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Aredia90mgpowderandsolventforconcentrateforsolutionforinfusion.

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom13/08/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Aredia90mgpowderandsolventforconcentrateforsolutionforinfusion.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Each90mgvialcontainslyophilisedpamidronatedisodiumpentahydrateequivalentto90mgpamidronatedisodium

anhydrous.

A10mlampouleofwaterforinjectionsissuppliedwitheachvial.Whenreconstituted,theconcentrationis9mg/ml.

Furtherdilutionisrequired.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Powderandsolventforconcentrateforsolutionforinfusion.(Powderandsolventforsterileconcentrate)

White,lyophilisedmass.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Directionsforuse:

Forthetreatmentoftumour-inducedosteolysiswithorwithouttumour-inducedhypercalcaemia.

ForthetreatmentofPaget’sdiseaseofbone.

4.2Posologyandmethodofadministration

Directionsforuse:

Forintravenousinfusion

Arediamustneverbegivenasabolusinjection.

Arediashouldalwaysbedilutedbeforeuseandadministeredasaslowintravenousinfusion.

PreparationofInfusion:

Thisisatwostepprocedure:

Usingaseptictechnique,Arediadrypowder90mgshouldbedissolvedin10mlofWaterforInjections

Ph.Eur.Itisimportantthatthedrysubstanceiscompletelydissolvedbeforeproceedingtostep2.

Thereconstitutedsolutioniswithdrawnfordilution.ReconstitutionsolutionofArediafrompowderinvials

shouldbedilutedinacalcium-freeinfusionsolution(0.9%sodiumchlorideor5%glucose).Theinfusionrateshould

notexceed60mgin1hour(1mg/min)andtheconcentrationofArediaintheinfusionsolutionshouldnotexceed

90mg/250ml.Adoseof90mgshouldnormallybeadministeredasa2-hourinfusionin250mlinfusionsolution.

However,inpatientswithtumour-inducedhypercalcaemia,itisrecommendednottoexceed90mgin500mlover4

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Inordertominimiselocalreactionsattheinfusionsite;thecannulashouldbecarefullyinsertedintoarelativelylarge

vein.

AdultsandtheElderly:

Tumour-InducedOsteolysis

Therecommendeddoseis30mgonceaweekforfourconsecutiveweeksandthenonceeverytwoweeks,forsix

months,oruntilthereisevidenceofdiseaseprogressioninthebone,whenpatientmanagementshouldbereassessed.

Ifpatientsprogresstoclinicallysignificanthypercalcaemia,thefollowingregimeshouldbeadopted.

Tumour-InducedHypercalcaemia

PatientsmustbeadequatelyrehydratedpriortoandduringadministrationofAredia.ThetotaldoseofArediatobe

usedforatreatmentcoursedependsonthepatient’sinitialserumcalciumlevel.

Thefollowingguidelinesarederivedfromclinicaldataonuncorrectedcalciumvalues.However,dosesintheranges

givenarealsoapplicableforcalciumcorrectedfortotalproteinoralbumininrehydratedpatients:

Adoseof30to60mghasbeenfoundtobeappropriateforthemajorityofpatients.ThetotaldoseofArediamaybe

administeredeitherinasingleinfusionorinmultipleinfusionsover2to4consecutivedays.Themaximumdoseper

treatmentcourseofArediais90mgforbothinitialandrepeatcourses.Patientexperienceindicatesthatdosesabove

90mgbringnoincreasedclinicalbenefit.

Asignificantdecreaseinserumcalciumisgenerallyobserved24to48hoursafteradministrationandnormalisationis

usuallyachievedwithin3to7days.Ifnormocalcaemiaisnotachievedwithinthistime,afurtherdosemaybegiven.

Thedurationoftheresponsemayvaryfrompatienttopatient,andtreatmentcanberepeatedwheneverhypercalcaemia

recurs.ClinicalexperiencetodatesuggeststhatArediamaybelesseffectiveasthenumberoftreatmentsincreases.

Paget’sDiseaseofBone

Treatmentshouldbemadeunderthesupervisionofahospitalbasedspecialist.Therecommendedtreatmentcourse

consistsof180mgadministeredinunitdosesofeither30mgonceaweekfor6consecutiveweeksor60mgeveryother

weekoverthreeweeks.

Experiencetodatesuggeststhatanymildortransientunwantedeffects(Seesideeffects)tendtooccurafterthefirst

dose.Forthisreasonifunitdosesof60mgareused,itisrecommendedthattreatmentbestartedwithaninitialdoseof

30mg(totaldose210mg).

Theregimenorincreaseddoselevelsaccordingtodiseaseseverity,uptoamaximumtotaldoseof360mg(omittingthe

initial30mgdose),canberepeatedevery6monthsuntilremissionofdiseaseisachievedandifrelapseoccurs.

Renalimpairment:

Arediashouldnotbeadministeredtopatientswithsevererenalimpairment(creatinineclearance<30mL/min)unless

incasesoflife-threateningtumour-inducedhypercalcaemiawherethebenefitoutweighsthepotentialrisk.

InitialSerumCalcium Recommendedtotaldose(mg)

(mmol/L) (mg%)

Upto3.0

3.0-3.5

3.5-4.0

>4.0 Upto12.0

12.0–14.0

14.0–16.0

>16.0 15–30

30–60

60–90

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priortoeachdoseofAredia.InpatientsreceivingArediaforbonemetastaseswhoshowevidenceofdeteriorationin

renalfunction,Arediatreatmentshouldbewithhelduntilrenalfunctionreturnstowithin10%ofthebaselinevalue.

Thisrecommendationisbasedonaclinicalstudy,inwhichrenaldeteriorationwasdefinedasfollows:

Forpatientswithnormalbaselinecreatinine,increaseof0.5mg/dL.

Forpatientswithabnormalbaselinecreatinine,increaseof1.0mg/dL.

Apharmacokineticstudyconductedinpatientswithcancerandnormalorimpairedrenalfunctionindicatesthatthe

doseadjustmentisnotnecessaryinmild(creatinineclearance61–to90mL/min)tomoderaterenalimpairment

(creatinineclearance30–to60mL/min).Insuchpatients,theinfusionrateshouldnotexceed90mg/4h(approximately

20–to22mg/h).

HepaticImpairment:

Apharmacokineticstudyindicatesthatnodoseadjustmentisnecessaryinpatientswithmildtomoderateabnormal

hepaticfunction(seesection5.2.-Pharmacokineticproperties–Hepaticimpairment).Arediahasnotbeenstudiedin

patientswithseverehepaticimpairment(seesection4.4Specialwarningsandprecautionsforuse).

Children:

ThereisnoclinicalexperienceofArediainchildren.

4.3Contraindications

Arediaiscontraindicated

Inpatientswithknownhypersensitivitytopamidronatedisodiumorotherbisphosphonates,ortoanyofthe

excipientsofAredia.

Inpregnancy.

Inbreast-feedingwomen.

4.4Specialwarningsandprecautionsforuse

General:

Arediamustneverbegivenasabolusinjectionsincelocalreactionsandthrombophlebitismayoccur.Arediashould

alwaysbedilutedandgivenasaslowintravenousinfusion.(SeeSection4.2PosologyandMethodofAdministration).

PatientsmustbeassessedpriortoadministrationofArediatoassurethattheyareappropriatelyhydrated.Thisis

especiallyimportantforpatientsreceivingdiuretictherapy.

Standardhypercalcaemia-relatedmetabolicparametersincludingserumcalciumandphosphateshouldbemonitored

followingintiationoftherapywithAredia.Patientswhohaveundergonethyroidsurgerymaybeparticularly

susceptibletodevelophypocaicaemiaduetorelativehypoparathyroidism.

Inpatientswithcardiacdiseaseespeciallyintheelderly,additionalsalineoverloadmayprecipitatecardiacfailure(left

ventricularfailureorcongestiveheartfailure).Fever(influenzalikesymptoms)mayalsocontributetothis

deterioration.

RenalInsufficiency:

Bisphosphonates,includingAredia,havebeenassociatedwithrenaltoxicitymanifestedasdeteriorationofrenal

functionandpotentialrenalfailure.Renaldeterioration,progressiontorenalfailureanddialysishavebeenreportedin

patientsaftertheinitialdoseorasingledoseofAredia.Deteriorationofrenalfunction(includingrenalfailure)has

beenreportedfollowinglong-termtreatmentwithArediainpatientswithmultiplemyeloma.

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reactionsmaybegreaterinpatientswithimpairedrenalfunction.

Duetotheriskofclinicallysignificantdeteriorationinrenalfunctionwhichmayprogresstorenalfailure,singledoses

ofArediashouldnotexceed90mg,andtherecommendedinfusiontimeshouldbeobserved(SeeSection4.2Posology

andmethodofadministration).

Aswithotheri.v.bisphosphonatesrenalmonitoringisrecommended,forinstance,measurementofserumcreatinine

priortoeachdoseofAredia.

PatientsreceivingfrequentinfusionsofArediaoveraprolongedperiodoftime,especiallythosewithpre-existingrenal

diseaseorapredispositiontorenalimpairment(e.g.patientswithmultiplemyelomaand/ortumourinduced

hypercalcaemia)shouldhaveevaluationsofstandardlaboratoryandclinicalparametersofrenalfunctionpriortoeach

doseofAredia.

PatientstreatedwithArediaforbonemetastasesshouldhavethedosewithheldifrenalfunctionhasdeteriorated(see

section4.2Posologyandmethodofadministration).

ThereisverylittleexperienceoftheuseofArediainpatientsreceivinghaemodialysis.

Arediashouldnotbegivenwithotherbisphosphonatesbecausetheircombinedeffectshavenotbeeninvestigated.

Thereisapossibilityofprecipitatingconvulsionsinsomepatientsduetotheelectrolytechangesassociatedwith

tumour-inducedhypercalcaemiaanditseffectivetreatment.

HepaticInsufficiency:

Astherearenoclinicaldataavailableinpatientswithseverehepaticinsufficiency,nospecificrecommendationscanbe

givenforthispatientpopulation(seesection4.2Posologyandmethodofadministrationand5.2Pharmacokinetic

properties).

CalciumandVitaminDsupplementation:

Intheabsenceofhypercalcaemia,patientswithpredominantlylyticbonemetastasesormultiplemyelomawhoareat

riskofcalciumorvitamindeficiencyandpatientswithPaget’sdiseaseoftheboneshouldtakeoralcalciumand

vitaminDsupplementsinordertominimisetheriskofhypocalcaemia.

OsteonecrosisoftheJaw:

Osteonecrosisofthejaw(ONJ)hasbeenreportedpredominantlyincancerpatientstreatedwithbisphosphonates,

includingAredia.Manyofthesepatientswerealsoreceivingchemotherapyandcorticosteroids.Themajorityof

reportedcaseshavebeenassociatedwithdentalproceduressuchastoothextraction.Manyhadsignsoflocalinfection

includingosteomyelitis.

Post-marketingexperienceandtheliteraturesuggestagreaterfrequencyofreportsofONJbasedontumortype

(advancedbreastcancer,multiplemyeloma),anddentalstatus(dentalextraction,periodontaldisease,localtrauma

includingpoorlyfittingdentures).

Cancerpatientsshouldmaintaingoodoralhygieneandshouldhaveadentalexaminationwithpreventativedentistry

priortotreatmentwithbisphosphonates

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbisphosphonatetherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbisphosphonatetreatment

reducestheriskofosteonecrosisofthejaw.Clinicaljudgementofthetreatingphysicianshouldguidethemanagement

planofeachpatientbasedonindividualbenefit/riskassessment.

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Inpost-marketingexperience,severeandoccasionallyincapacitatingbone,jointand/ormusclepainhasbeenreported

inpatientstalkingbisphosphonates.However,suchreportshavebeeninfrequent.Thiscategoryofdrugsincludes

Aredia(pamidronatedisodiumforinfusion).Thetimetoonsetofsymptomsvariedfromonedaytoseveralmonths

afterstartingthedrug.Mostpatientshadreliefofsymptomsafterstoppingtreatment.Asubsethadrecurrenceof

symptomswhenrechallengedwiththesamedrugoranotherbisphosphonate.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Arediahasbeenadministeredconcomitantlywithcommonlyusedanti-canceragentswithoutinteractionoccurring.

Arediashouldnotbeco-administeredwithotherbisphosphonatesbecausetheircombinedeffectshavenotbeen

investigated.

Arediahasbeenusedincombinationwithcalcitonininpatientswithseverehypercalcaemia,resultinginasynergistic

effectproducingamorerapidfallinserumcalcium.

Sincepamidronatebindstobone,itcouldintheoryinterferewithbonescintigraphyexaminations.

CautioniswarrantedwhenArediaisusedwithotherpotentiallynephrotoxicdrugs.

Inmultiplemyelomapatients,theriskofrenaldisfunctionmaybeincreasedwhenArediaisusedincombinationwith

thalidomide.

4.6Pregnancyandlactation

IthasbeenshownthatArediacancrosstheplacentainratsandhasproducedmarkedmaternalandnon-teratogenic

embryo/fetaleffectsinratsandrabbits(seesection5.3Preclincalsafetydata).

Therearenoadequateandwell-controlledstudiesinpregnantwomenandnoclinicalexperiencetosupporttheuseof

Arediainpregnantwomen. Therefore,Arediashouldnotbeusedduringpregnancy(seesection4.3

Contraindications).

Astudyinlactatingratshasshownthatpamidronatewillpassintothemilk.MotherstreatedwithArediashould

thereforenotbreast-feedtheirinfants(seesection4.3Contraindications)

4.7Effectsonabilitytodriveandusemachines

Patientsshouldbewarnedthatinrarecasessomnolenceand/ordizzinessmayoccurfollowingArediainfusion,in

whichcasetheyshouldnotdrive,operatepotentiallydangerousmachinery,orengageinotheractivitiesthatmaybe

hazardousbecauseofdecreasedalertness.

4.8Undesirableeffects

AdversereactionstoArediaareusuallymildandtransient.Themostcommonadversereactionsareasymptomatic

hypocalcaemiaandfever(anincreaseinbodytemperatureof1-2 °

C),typicallyoccurringwithinthefirst48hoursof

infusion.Feverusuallyresolvesspontaneouslyanddoesnotrequiretreatment.

Frequencyestimate:Verycommon(>1/10),common(>1/100,<1/10),uncommon(>1/1,000,<1/100),rare(>1/10,000,

<1/1,000),veryrare(<1/10,000),includingisolatedreports.

Table2

InfectionsandInfestations

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Bloodandlymphaticsystemsdisorders

Common: Anaemia,thrombocytopenia,lymphocytopenia.

Veryrare: Leukopenia.

Immunesystemdisorders

Uncommon: Allergicreactionsincludinganaphylactoidreactions,

bronchospasm/dyspnoea,Quincke’s(angioneurotic)

oedema.

Veryrare: Anaphylacticshock

MetabolismandNutritionaldisorders

Verycommon: Hypocalcaemia,hypophosphataemia

Common: Hypokalaemia,hypomagnesaemia

Veryrare: Hyperkalaemia,hypernatraemia

Nervoussystemdisorders

Common: Symptomatichypocalcemia(paresthesia,tetany),

headache,insomnia,somnolence.

Uncommon: Seizures,agitation,dizziness,lethargy.

Veryrare: Confusion,visualhallucinations.

Eyedisorders

Common: Conjunctivitis.

Uncommon: Uveitis(iritis,iridocyclitis).

Veryrare: Scleritis,episcleritis,xanthopsia.

Cardiacdisorders

Veryrare: Leftventricularfailure(dyspnoea,pulmonaryoedema),

congestiveheartfailure(oedema)duetofluidoverload.

Vasculardisorders

Common: Hypertension

Uncommon: Hypotension

Gastrointestinaldisorders

Common: Nausea,vomiting,anorexia,abdominalpain,diarrhoea,

constipation,gastritis.

Uncommon: Dyspepsia.

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Manyoftheseundesirableeffectsmayhavebeenrelatedtotheunderlyingdisease.

Atrialfibrillation:Whentheeffectsofzoledronicacid(4mg)andpamidronate(90mg)werecomparedinoneclinical

trial,thenumberofatrialfibrillationadverseeventswashigherinthepamidronategroup(12/556,2.2%)thaninthe

zoledronicacidgroup(3/563,0.5%).Isolatedinstancesofhigherincidenceofatrialfibrillationhavealsobeenreported

inafewstudieswithotherbisphosphonates.Themechanismofthisincreasedincidenceofatrialfibrillationinisolated

studieswithsomebisphosponates,includingAredia,isunknown.

Post-marketingexperience:

Thefollowingadversereactionshavebeenreportedduringpost-approvaluseofAredia.Becausethesereportsarefrom

apopulationofuncertainsizeandaresubjecttoconfoundingfactors,itisnotpossibletoreliablyestimatetheir

frequencyorestablishacausalrelationshiptodrugexposure.

Casesofosteonecrosis(primarilyofthejaws)havebeenreportedpredominantlyincancerpatientstreatedwith

bisphosphonates,includingAredia(uncommon).Manyofthesepatientshadsignsoflocalinfectionincluding

osteomyelitisandthemajorityofthereportsrefertocancerpatientsfollowingtoothextractionsorotherdental

surgeries.

Osteonecrosisofthejawshasmultiplewelldocumentedriskfactorsincludingadiagnosisofcancer,concomitant

therapies(e.g.chemotherapy,radiotherapy,corticosteroids)andco-morbidconditions(e.g.anaemia,coagulopathies,

infection,pre-existingoraldisease).Althoughcausalityhasnotbeendetermined,itisprudenttoavoiddentalsurgery

asrecoverymaybeprolonged(seesection4.4Specialwarningsandprecautionsforuse).Datasuggestagreater

frequencyofreportsofONJbasedontumourtype(advancedbreastcancer,multiplemyeloma).

Common: Rash.

Uncommon: Pruritus.

Musculoskeletalandconnectivetissuedisorders

Common: Transientbonepain,arthralgia,myalgia,generalised

pain.

Uncommon: Musclecramps.

Renalandurinarydisorders

Uncommon: Acuterenalfailure.

Rare: Focalsegmentalglomerulosclerosisincludingthe

collapsingvariant,nephroticsyndrome

Veryrare: Deteriorationofpre-existingrenaldisease,haematuria.

Generaldisordersandadministrationsiteconditions

VeryCommon: Feverandinfluenza-likesymptomssometimes

accompaniedbymalaise,rigor,fatigue,andflushes.

Common: Reactionsattheinfusionsite(pain,redness,swelling,

induration,phlebitis,thrombophlebitis).

Investigations

Common: Increaseinserumcreatinine.

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4.9Overdose

ThereisnoexperienceofoverdosagewithAredia.

Symptoms:Overdosagewouldbeclinicallymanifestedasthesignsandsymptomsofhypocalcaemia,i.e.paraesthesia

andcarpopedalspasm.

Treatment:Intheeventofclinicallysignificanthypocalcaemia,reversalmaybeachievedwithaninfusionofcalcium

gluconate.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Inhibitorofboneresorption(ATCcode:M05BA03)

Pamidronatedisodium,theactivesubstanceofAredia,isapotentinhibitorofosteoclasticboneresorption.Itbinds

stronglytohydroxyapatitecrystalsandinhibitstheformationanddissolutionofthesecrystalsinvitro.Inhibitionof

osteoclasticboneresorptioninvivomayatleastinpartbeduetobindingofthedrugtothebonemineral.

Pamidronatesuppressestheaccessionoftheosteoclastprecursorsontotheboneandtheirsubsequenttransformation

intomatureresorbingosteoclasts.Howeverthelocalanddirectantiresorptiveeffectofbone-boundbisphosphonate

appearstobethepredominantmodeofactioninvitroandinvivo.

ExperimentalstudiesinanimalshavedemonstratedthatArediainhibitstumour-inducedosteolysiswhengivenpriorto,

oratthetimeofinoculationortransplantationwithtumourcells.Biochemicalchangesreflectingtheinhibitoryeffect

ofArediaontumour-inducedosteolysis,andspecificallyontumour-inducedhypercalcaemia,arecharacterisedbya

decreaseinserumcalciumand,secondarilybydecreaseinurinaryexcretionofcalcium,phosphate,and

hydroxyproline.

Hypercalcaemiacanleadtoadepletioninvolumeofextracellularfluidandareductionintheglomerularfiltrationrate

(GFR).Bycontrollinghypercalcaemia,ArediaimprovesGFRandlowerselevatedserumcreatininelevelsinmost

patients.

Paget’sdiseaseofbone,whichischaracterisedbylocalareasofincreasedboneresorptionandformationwith

qualitativechangesinboneremodelling.

5.2Pharmacokineticproperties

Generalcharacteristics

Pamidronatehasastrongaffinityforcalcifiedtissues,andtotaleliminationofpamidronatefromthebodyisnot

observedwithinthetimeframeofexperimentalstudies.Calcifiedtissuesarethereforeregardedassiteof“apparent

elimination”.

Absorption

Pamidronatedisodiumisgivenbyintravenousinfusion.Bydefinition,absorptioniscompleteattheendofinfusion.

Distribution

Plasmaconcentrationsofpamidronateriserapidlyafterthestartofaninfusionandfallrapidlywhentheinfusionis

stopped.Theapparenthalf-lifeinplasmaisabout0.8hours.Apparentsteady-stateconcentrationsaretherefore

achievedwithinfusionsofmorethanabout2–to3hours’duration.Peakplasmapamidronateconcentrationsofabout

10nmol/mLareachievedafteranintravenousinfusionof60mggivenover1hour.

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disodium.Thustheaccumulationofpamidronateinboneisnotcapacity-limited,andisdependentsolelyonthetotal

cumulativedoseadministered.

Thepercentageofcirculatingpamidronateboundtoplasmaproteinsisrelativelylow(about54%),andincreaseswhen

calciumconcentrationsarepathologicallyelevated.

Elimination

Pamidronatedoesnotappeartobeeliminatedbybiotransformation.Afteranintravenousinfusion,about20–to55%

ofthedoseisrecoveredintheurinewithin72hoursasunchangedpamidronate.

Withinthetimeframeofexperimentalstudiestheremainingfractionofthedoseisretainedinthebody.The

percentageofthedoseretainedinthebodyisindependentofboththedose(range15–to180mg)andtheinfusionrate

(range1.25–to60mg/hour).Theeliminationofpamidronateintheurineisbiexponential,withapparenthalf-livesof

about1.6and27hours.

Theapparenttotalplasmaclearanceisabout180ml/minandtheapparentrenalclearanceisabout54mL/min,andthere

isatendencyfortherenalclearancetocorrelatewithcreatinineclearance.

Characteristicsinpatients

Hepaticandmetabolicclearancesofpamidronateareinsignificant.Impairmentofliverfunctionisthereforenot

expectedtoinfluencethepharmacokineticsofAredia.Arediathusdisplayslittlepotentialfordrug-druginteractions

bothatthemetaboliclevelandatthelevelofproteinbinding(seeabove).

Hepaticimpairment

Thepharmacokineticsofpamidronatewerestudiedinmalecancerpatientsatriskforbonemetastaseswithnormal

hepaticfunction(n=6)andmildtomoderatehepaticdysfunction(n=9).Eachpatientreceivedasingle90mgdoseof

Arediainfusedover4hours.Althoughtherewasastatisticallysignificantdifferenceinthepharmacokineticsbetween

patientswithnormalandimpairedhepaticfunction,thedifferencewasnotconsideredclinicallyrelevant.Patientswith

hepaticimpairmentexhibitedhighermeanAUC(39,7%)andCmax(28,6%)values.Nevertheless,pamidronatewas

stillrapidlyclearedfromtheplasma.Druglevelswerenotdetectableinpatientsby12–to36hoursafterdruginfusion.

BecauseArediaisadministeredonamonthlybasis,drugaccumulationisnotexpected.NochangesinArediadosing

regimenarerecommendedforpatientswithmildtomoderateabnormalhepaticfunction(see4.2.Posologyandmethod

ofadministration).

Renalimpairment:

ApharmacokineticstudyconductedinpatientswithcancershowednodifferencesinplasmaAUCofpamidronate

betweenpatientswithnormalrenalfunctionandpatientswithmildtomoderaterenalimpairment.Inpatientswith

severerenalimpairment(creatinineclearance<30mL/min),theAUCofpamidronatewasapproximately3times

higherthaninpatientswithnormalrenalfunction(creatinineclearance>90mL/min).

5.3Preclinicalsafetydata

Thetoxicityofpamidronateischaracterisedbydirect(cytotoxic)effectsonorganswithacopiousbloodsupply,

particularlythekidneysfollowingi.v.exposure.Thecompoundisnotmutagenicanddoesnotappeartohave

carcinogenicpotential.

Bolusintravenousstudiesconductedinratsandrabbitsdeterminedthatpamidronateproducesmaternaltoxicityand

embryo/fetaleffectswhengivenduringorganogenesisatdosesof0.6to8.3timesthehighestrecommendedhuman

doseforasingleintravenousinfusion.Asithasbeenshownthatpamidronatecancrosstheplacentainratsandhas

producedmarkedmaternalandnonteratogenicembryo/fetaleffectsinratsandrabbits,itshouldnotbegiventowomen

duringpregnancy.

Bisphosphonatesareincorporatedintothebonematrix,fromwheretheyaregraduallyreleasedoverperiodsofweeks

toyears.Theextentofbisphosphonateincorporationintoadultbone,andhence,theamountavailableforreleaseback

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verylimiteddatasuggestthatuptakeofbisphosphonatesintofetalboneisgreaterthanintomaternalbone.Therefore,

thereisatheoreticalriskoffetalharm(e.g.,skeletalandotherabnormalities)ifawomanbecomespregnantafter

completingacourseofbisphosphonatetherapy.Theimpactofvariablessuchastimebetweencessationof

bisphosphonatetherapytoconception,theparticularbisphosphonateused,andtherouteofadministration(intravenous

versusoral)onthisriskhasnotbeenestablished.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Vials

Mannitol

Phosphoricacid(forpHadjustment)

Ampoules

WaterforInjections.

6.2Incompatibilities

Arediamustnotbeadmixedwithcalcium-containinginfusionsolutions,e.g.Ringers,Hartmann’ssolution.

6.3ShelfLife

3years.

Usedilutedsolutionsimmediatelyanddiscardanysolutionremainingafteruse.

6.4Specialprecautionsforstorage

Donotstoreabove30 0

6.5Natureandcontentsofcontainer

Clear,colourlesssealedglassTypeIII(Ph.Eur.)10mlvialwithbromobutylrubberclosure,packagedinacardboard

carton.AclearcolourlessTypeI(Ph.Eur.)glassampoulecontainingsolventforreconstitution.

Packcontains1ArediaDryPowder90mlvialandone10mlampouleofWaterforInjections.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Powderinvialsshouldbefirstdissolvedinwaterforinjections,i.e.90mgin10ml.Thesterilewaterforinjectionsis

availableinampouleswhicharesuppliedtogetherwithvials.Theappearanceofthereconstitutedsolutionisclearand

shouldbefreefromanyundissolvedparticles.ThepHofthereconstitutedsolutionis6.0–7.0.

Thereconstitutedsolutionshouldbefurtherdilutedwithcalciumfreeinfusionsolution(0.9%sodiumchlorideor5%

glucose)beforeadministration.Itisimportantthatthepowderbecompletelydissolvedbeforethereconstitutedsolution

iswithdrawnfordilution.

Discardanyunusedsolutionremainingafteruse.

Irish Medicines Board

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Date Printed 13/08/2010 CRN 2081182 page number: 11

NovartisPharmaceuticalsUKLimited

FrimleyBusinessPark

Frimley

Camberley

SurreyGU165SG

England

8MARKETINGAUTHORISATIONNUMBER

PA0013/090/004

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:5July1995

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/08/2010 CRN 2081182 page number: 12

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 13/08/2010 CRN 2081182 page number: 13