BONEFURBIT

Main information

  • Trade name:
  • BONEFURBIT Film Coated Tablet 150 Base Milligrams
  • Dosage:
  • 150 Base Milligrams
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • BONEFURBIT Film Coated Tablet 150 Base Milligrams
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1239/012/001
  • Authorization date:
  • 12-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Bonefurbit150mgFilm-CoatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains150mgibandronicacid(asibandronatesodiumhydrate).

Excipients:

Eachfilm-coatedtabletcontains88.60mglactosemonohydrate.Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Whitefilm-coatedtabletsofoblongshapeandscored“LC”ononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofosteoporosisinpostmenopausalwomenatincreasedriskoffracture(seesection5.1).

Areductionintheriskofvertebralfractureshasbeendemonstrated,efficacyonfemoralneckfractureshasnotbeen

established.

4.2Posologyandmethodofadministration

Posology:

Therecommendeddoseisone150mgfilm-coatedtabletonceamonth.Thetabletshouldpreferablybetakenonthe

samedateeachmonth.

Bonefurbitshouldbetakenafteranovernightfast(atleast6hours)and1hourbeforethefirstfoodordrink(otherthan

water)oftheday(seesection4.5)oranyotheroralmedicinalproductsorsupplementation(includingcalcium).

Incaseadoseismissed,patientsshouldbeinstructedtotakeoneBonefurbit150mgtabletthemorningafterthetablet

isremembered,unlessthetimetothenextscheduleddoseiswithin7days.Patientsshouldthenreturntotakingtheir

doseonceamonthontheiroriginallyscheduleddate.

Ifthenextscheduleddoseiswithin7days,patientsshouldwaituntiltheirnextdoseandthencontinuetakingone

tabletonceamonthasoriginallyscheduled.

Patientsshouldnottaketwotabletswithinthesameweek.

Patientsshouldreceivesupplementalcalciumand/orvitaminDifdietaryintakeisinadequate(seesection4.4and

section4.5).

SpecialPopulations

Patientswithrenalimpairment

Nodoseadjustmentisnecessaryforpatientswithmildormoderaterenalimpairmentwherecreatinineclearanceis

equalorgreaterthan30ml/min.

Bonefurbitisnotrecommendedforpatientswithacreatinineclearancebelow30ml/minduetolimitedclinical

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Patientswithhepaticimpairment

Nodoseadjustmentisrequired(seesection5.2).

ElderlyPopulation

Nodoseadjustmentisrequired(seesection5.2).

PaediatricPopulation

ThereisnorelevantuseofBonefurbitinchildren,andBonefurbitwasnotstudiedinthepaediatricpopulation.

MethodofAdministration:

Fororaluse.

Tabletsshouldbeswallowedwholewithaglassofplainwater(180to240ml)whilethepatientissittingorstandingin

anuprightposition.Patientsshouldnotliedownfor1houraftertakingBonefurbit.

PlainwateristheonlydrinkthatshouldbetakenwithBonefurbit.Pleasenotethatsomemineralwatersmayhavea

higherconcentrationofcalciumandtherefore,shouldnotbeused.

Patientsshouldnotcheworsuckthetablet,becauseofapotentialfororopharyngealulceration.

4.3Contraindications

Abnormalitiesoftheoesophaguswhichdelayoesophagealemptyingsuchasstrictureorachalasia.

Inabilitytostandorsituprightforatleast60minutes.

Hypocalcaemia(seesection4.4).

Hypersensitivitytoibandronicacidortoanyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

GastrointestinalDisorders

Orallyadministeredbisphosphonatesmaycauselocalirritationoftheuppergastrointestinalmucosa.Becauseofthese

possibleirritanteffectsandapotentialforworseningoftheunderlyingdisease,cautionshouldbeusedwhen

Bonefurbitisgiventopatientswithactiveuppergastrointestinalproblems(e.g.knownBarrett’soesophagus,

dysphagia,otheroesophagealdiseases,gastritis,duodenitisorulcers).

Adverseexperiencessuchasoesophagitis,oesophagealulcersandoesophagealerosions,insomecasessevereand

requiringhospitalisation,rarelywithbleedingorfollowedbyoesophagealstrictureorperforation,havebeenreported

inpatientsreceivingtreatmentwithoralbisphosphonates.Theriskofsevereoesophagealadverseexperiencesappears

tobegreaterinpatientswhodonotcomplywiththedosinginstructionand/orwhocontinuetotakeoral

bisphosphonatesafterdevelopingsymptomssuggestiveofoesophagealirritation.Patientsshouldpayparticular

attentiontoandbeabletocomplywiththedosinginstructions(seesection4.2).

Physiciansshouldbealerttoanysignsorsymptomssignallingapossibleoesophagealreactionandpatientsshouldbe

instructedtodiscontinueBonefurbitandseekmedicalattentioniftheydevelopdysphagia,odynophagia,retrosternal

painorneworworseningheartburn.

Whilenoincreasedriskwasobservedincontrolledclinicaltrialstherehavebeenpost-marketingreportsofgastricand

duodenalulcerswithoralbisphosphonateuse,somesevereandwithcomplications.

SinceNonsteroidalAnti-InflamatoryDrugsandbisphosphonatesarebothassociatedwithgastrointestinalirritation,

cautionshouldbetakenduringconcomitantadministration.

Hypocalcaemia

ExistinghypocalcaemiamustbecorrectedbeforestartingBonefurbittherapy.Otherdisturbancesofboneandmineral

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Renalimpairment

Duetolimitedclinicalexperience,Bonefurbitisnotrecommendedforpatientswithacreatinineclearancebelow30

ml/min(seesection5.2).

OsteonecrosisoftheJaw

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimensincludingprimarilyintravenouslyadministered

bisphosphonates.Manyofthesepatientswerealsoreceivingchemotherapyandcorticosteroids.Osteonecrosisofthe

jawhasalsobeenreportedinpatientswithosteoporosisreceivingoralbisphosphonates.

Adentalexaminationwithappropriatepreventivedentistryshouldbeconsideredpriortotreatmentwith

bisphosphonatesinpatientswithconcomitantriskfactors(e.g.cancer,chemotherapy,radiotherapy,corticosteroids,

poororalhygiene).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbisphosphonatetherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbisphosphonatetreatment

reducestheriskofosteonecrosisofthejaw.Clinicaljudgementofthetreatingphysicianshouldguidethemanagement

planofeachpatientbasedonindividualbenefit/riskassessment.

Galactoseintolerance

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Oralbioavailabilityofibandronicacidisgenerallyreducedinthepresenceoffood.Inparticular,productscontaining

calciumandothermultivalentcations(suchasaluminium,magnesium,iron),includingmilk,arelikelytointerfere

withabsorptionofBonefurbit,whichisconsistentwithfindingsinanimalstudies.Therefore,patientsshouldfast

overnight(atleast6hours)beforetakingBonefurbitandcontinuefastingfor1hourfollowingintakeofBonefurbit(see

section4.2).

Calciumsupplements,antacidsandsomeoralmedicinalproductscontainingmultivalentcations(suchasaluminium,

magnesium,iron)arelikelytointerferewiththeabsorptionofBonefurbit.Therefore,patientsshouldnottakeotheroral

medicinalproductsforatleast6hoursbeforetakingBonefurbitandfor1hourfollowingintakeofBonefurbit.

Metabolicinteractionsarenotconsideredlikely,sinceibandronicaciddoesnotinhibitthemajorhumanhepaticP450

isoenzymesandhasbeenshownnottoinducethehepaticcytochromeP450systeminrats.Furthermore,plasmaprotein

bindingisapproximately85%-87%(determinedinvitroattherapeuticconcentrations),andthusthereisalow

potentialforinteractionwithothermedicinalproductsduetodisplacement.Ibandronicacidiseliminatedbyrenal

excretiononlyanddoesnotundergoanybiotransformation.Thesecretorypathwayappearsnottoincludeknownacidic

orbasictransportsystemsinvolvedintheexcretionofotheractivesubstances.

Inatwo-yearstudyinpostmenopausalwomenwithosteoporosis(BM16549),theincidenceofuppergastrointestinal

eventsinpatientsconcomitantlytakingaspirinorNSAIDswassimilarinpatientstakingibandronicacid2.5mgdaily

or150mgoncemonthlyafteroneandtwoyears.

Ofover1500patientsenrolledinstudyBM16549comparingmonthlywithdailydosingregimensofibandronicacid,

14%and18%ofpatientsusedhistamine(H2)blockersorprotonpumpinhibitorsafteroneandtwoyears,

respectively.Amongthesepatients,theincidenceofuppergastrointestinaleventsinthepatientstreatedwithibandronic

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Inhealthymalevolunteersandpostmenopausalwomen,intravenousadministrationofranitidinecausedanincreasein

ibandronicacidbioavailabilityofabout20%,probablyasaresultofreducedgastricacidity.However,sincethis

increaseiswithinthenormalvariabilityofthebioavailabilityofibandronicacid,nodoseadjustmentisconsidered

necessarywhenBonefurbitisadministeredwithH2-antagonistsorotheractivesubstanceswhichincreasegastricpH.

Pharmacokineticinteractionstudiesinpostmenopausalwomenhavedemonstratedtheabsenceofanyinteraction

potentialwithtamoxifenorhormonereplacementtherapy(oestrogen).

Nointeractionwasobservedwhenco-administeredwithmelphalan/prednisoloneinpatientswithmultiplemyeloma.

4.6Fertility,pregnancyandlactation

Pregnancy

Therearenoadequatedatafromtheuseofibandronicacidinpregnantwomen.Studiesinratshaveshownsome

reproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.

Bonefurbitshouldnotbeusedduringpregnancy.

Lactation

Itisnotknownwhetheribandronicacidisexcretedinhumanmilk.Studiesinlactatingratshavedemonstratedthe

presenceoflowlevelsofibandronicacidinthemilkfollowingintravenousadministration.

Bonefurbitshouldnotbeusedduringlactation.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.

4.8Undesirableeffects

Thesafetyoforaltreatmentwithibandronicacid2.5mgdailywasevaluatedin1251patientstreatedin4placebo-

controlledclinicalstudies,withthelargemajorityofpatientscomingfromthepivotalthreeyearfracturestudy

(MF4411).

Theoverallsafetyprofileofibandronicacid2.5mgdailyinallthesestudieswassimilartothatofplacebo.

Inatwo-yearstudyinpostmenopausalwomenwithosteoporosis(BM16549)theoverallsafetyofibandronicacid

150mgoncemonthlyandibandronicacid2.5mgdailywassimilar.Theoverallproportionofpatientswhoexperienced

anadversereactionwas22.7%and25.0%foribandronicacid150mgoncemonthlyafteroneandtwoyears,

respectively.Themajorityofadversereactionsweremildtomoderateinintensity.Mostcasesdidnotleadtocessation

oftherapy.

Themostcommonlyreportedadversereactionwasarthralgia.

AdversereactionsconsideredbyinvestigatorstobecausallyrelatedtoIbandronicAcidLiconsaarelistedbelowby

SystemOrganClass.

Frequenciesaredefinedascommon( ≥1/100to<1/10),uncommon(≥1/1,000to<1/100),andrare(≥1/10,000to<

1/1,000).Withineachfrequencygrouping,adversereactionsarepresentedinorderofdecreasingseriousness.

Table1:AdversereactionsoccurringinpostmenopausalwomenreceivingIbandronicAcidLiconsa150mgonce

monthlyoribandronicacid2.5mgdailyinthephaseIIIstudiesBM16549andMF4411.

SystemOrganClass Frequency Adversereactions

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MedDRAversion12.0

*Transient,influenza-likesymptomshavebeenreportedwithibandronicacid150mgoncemonthly,typicallyin

associationwiththefirstdose.Suchsymptomsweregenerallyofshortduration,mildormoderateinintensity,and

resolvedduringcontinuingtreatmentwithoutrequiringremedialmeasures.Influenza-likeillnessincludesevents

reportedasacutephasereactionorsymptomsincludingmyalgia,arthralgia,fever,chills,fatigue,nausea,lossof

appetite,orbonepain.

Patientswithaprevioushistoryofgastrointestinaldiseaseincludingpatientswithpepticulcerwithoutrecentbleeding

orhospitalisation,andpatientswithdyspepsiaorrefluxcontrolledbymedicationwereincludedintheoncemonthly

treatmentstudy.Forthesepatients,therewasnodifferenceintheincidenceofuppergastrointestinaladverseevents

withthe150mgoncemonthlyregimencomparedtothe2.5mgdailyregimen.

Laboratorytestfindings

Inthepivotalthree-yearstudywithibandronicacid2.5mgdaily(MF4411)therewasnodifferencecomparedwith

placeboforlaboratoryabnormalitiesindicativeofhepaticorrenaldysfunction,animpairedhaematologicsystem,

hypocalcaemiaorhypophosphataemia.

Similarly,nodifferenceswerenotedbetweenthegroupsinstudyBM16549afteroneandtwoyears.

Post-marketingExperience

Osteonecrosisofthejawhasbeenreportedinpatientstreatedbybisphosphonates.Themajorityofthereportsreferto

cancerpatients,butsuchcaseshavealsobeenreportedinpatientstreatedforosteoporosis.Osteonecrosisofthejawis

generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis).Diagnosisofcancer,

chemotherapy,radiotherapy,corticosteroidsandpoororalhygienearealsodeemedasriskfactors(seesection4.4).

4.9Overdose

NospecificinformationisavailableonthetreatmentofoverdosagewithBonefurbit.

However,basedonaknowledgeofthisclassofcompounds,oralover-dosagemayresultinuppergastrointestinal

adversereactions(suchasupsetstomach,dyspepsia,oesophagitis,gastritis,orulcer)orhypocalcaemia.Milkor

antacidsshouldbegiventobindBonefurbit,andanyadversereactionstreatedsymptomatically.Owingtotheriskof

Nervoussystem

disorders Common Headache

Uncommon Dizziness

Gastrointestinaldisorders Common Oesophagitis,Gastritis,Gastro

oesophagealrefluxdisease,Dyspepsia,

Diarrhoea,Abdominalpain,Nausea

Uncommon Oesophagitisincludingoesophageal

ulcerationsorstricturesanddysphagia,

Vomiting,Flatulence

Rare Duodenitis

Skinandsubcutaneous

tissuedisorders Common Rash

Rare Angioedema,Faceoedema,Urticaria

Musculoskeletal,

connectivetissueand

bonedisorders Common Arthralgia,Myalgia,Musculoskeletal

pain,Musclecramp,Musculoskeletal

stiffness

Uncommon Backpain

Generaldisordersand

administrationsite

conditions Common Influenzalikeillness*

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5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Bisphosphonates,ATCcode:M05BA06

Mechanismofaction

Ibandronicacidisahighlypotentbisphosphonatebelongingtothenitrogen-containinggroupofbisphosphonates,

whichactselectivelyonbonetissueandspecificallyinhibitosteoclastactivitywithoutdirectlyaffectingbone

formation.Itdoesnotinterferewithosteoclastrecruitment.Ibandronicacidleadstoprogressivenetgainsinbonemass

andadecreasedincidenceoffracturesthroughthereductionofelevatedboneturnovertowardspremenopausallevelsin

postmenopausalwomen.

Pharmacodynamiceffects

Thepharmacodynamicactionofibandronicacidisinhibitionofboneresorption.Invivo,ibandronicacidprevents

experimentallyinducedbonedestructioncausedbycessationofgonadalfunction,retinoids,tumoursortumour

extracts.Inyoung(fastgrowing)rats,theendogenousboneresorptionisalsoinhibited,leadingtoincreasednormal

bonemasscomparedwithuntreatedanimals.

Animalmodelsconfirmthatibandronicacidisahighlypotentinhibitorofosteoclasticactivity.Ingrowingrats,there

wasnoevidenceofimpairedmineralizationevenatdosesgreaterthan5,000timesthedoserequiredforosteoporosis

treatment.

Bothdailyandintermittent(withprolongeddose-freeintervals)long-termadministrationinrats,dogsandmonkeys

wasassociatedwithformationofnewboneofnormalqualityandmaintainedorincreasedmechanicalstrengthevenat

dosesinthetoxicrange.Inhumans,theefficacyofbothdailyandintermittentadministrationwithadose-freeinterval

of9-10weeksofibandronicacidwasconfirmedinaclinicaltrial(MF4411),inwhichibandronicaciddemonstrated

anti-fractureefficacy.

Inanimalmodelsibandronicacidproducedbiochemicalchangesindicativeofdose-dependentinhibitionofbone

resorption,includingsuppressionofurinarybiochemicalmarkersofbonecollagendegradation(suchas

deoxypyridinoline,andcross-linkedN-telopeptidesoftypeIcollagen(NTX)).

InaPhase1bioequivalencestudyconductedin72postmenopausalwomenreceiving150mgorallyevery28daysfora

totaloffourdoses,inhibitioninserumCTXfollowingthefirstdosewasseenasearlyas24hourspost-dose(median

inhibition28%),withmedianmaximalinhibition(69%)seen6dayslater.Followingthethirdandfourthdose,the

medianmaximuminhibition6dayspostdosewas74%withreductiontoamedianinhibitionof56%seen28days

followingthefourthdose.Withnofurtherdosing,thereisalossofsuppressionofbiochemicalmarkersofbone

resorption.

Clinicalefficacy

Independentriskfactors,forexample,lowBMD,age,theexistenceofpreviousfractures,afamilyhistoryoffractures,

highboneturnoverandlowbodymassindexshouldbeconsideredinordertoidentifywomenatincreasedriskof

osteoporoticfractures.

Ibandronicacid150mgoncemonthly

Bonemineraldensity(BMD)

Ibandronicacid150mgoncemonthlywasshowntobeatleastaseffectiveasibandronicacid2.5mgdailyat

increasingBMDinatwoyear,double-blind,multicentrestudy(BM16549)ofpostmenopausalwomenwith

osteoporosis(lumbarspineBMDTscorebelow-2.5SDatbaseline).Thiswasdemonstratedinboththeprimary

analysisatoneyearandintheconfirmatoryanalysisattwoyearsendpoint(Table2).

Table2:Meanrelativechangefrombaselineoflumbarspine,totalhip,femoralneckandtrochanterBMDafterone

year(primaryanalysis)andtwoyearsoftreatment(Per-ProtocolPopulation)instudyBM16549.

OneyeardatainstudyBM16549 TwoyeardatainstudyBM

16549

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Furthermore,ibandronicacid150mgoncemonthlywasprovensuperiortoibandronicacid2.5mgdailyforincreases

inlumbarspineBMDinaprospectivelyplannedanalysisatoneyear,p=0.002,andattwoyears,p<0.001.

Atoneyear(primaryanalysis),91.3%(p=0.005)ofpatientsreceivingibandronicacid150mgoncemonthlyhada

lumbarspineBMDincreaseaboveorequaltobaseline(BMDresponders),comparedwith84.0%ofpatientsreceiving

ibandronicacid2.5mgdaily.Attwoyears,93.5%(p=0.004)and86.4%ofpatientsreceivingibandronicacid150mg

oncemonthlyoribandronicacid2.5mgdaily,respectively,wereresponders.

FortotalhipBMD,90.0%(p<0.001)ofpatientsreceivingibandronicacid150mgoncemonthlyand76.7%of

patientsreceivingibandronicacid2.5mgdailyhadtotalhipBMDincreasesaboveorequaltobaselineatoneyear.At

twoyears93.4%(p<0.001)ofpatientsreceivingibandronicacid150mgoncemonthlyand78.4%,ofpatients

receivingibandronicacid2.5mgdailyhadtotalhipBMDincreasesaboveorequaltobaseline.

Whenamorestringentcriterionisconsidered,whichcombinesbothlumbarspineandtotalhipBMD,83.9%

(p<0.001)and65.7%ofpatientsreceivingibandronicacid150mgoncemonthlyoribandronicacid2.5mgdaily,

respectively,wererespondersatoneyear.Attwoyears,87.1%(p<0.001)and70.5%,ofpatientsmetthiscriterionin

the150mgmonthlyand2.5mgdailyarmsrespectively.

Biochemicalmarkersofboneturn-over

ClinicallymeaningfulreductionsinserumCTXlevelswereobservedatalltimepointsmeasured,i.e.months3,6,12

and24.Afteroneyear(primaryanalysis)themedianrelativechangefrombaselinewas-76%foribandronicacid150

mgoncemonthlyand-67%foribandronicacid2.5mgdaily.Attwoyearsthemedianrelativechangewas-68%and-

62%,inthe150mgmonthlyand2.5mgdailyarmsrespectively.

Atoneyear,83.5%(p=0.006)ofpatientsreceivingibandronicacid150mgoncemonthlyand73.9%ofpatients

receivingibandronicacid2.5mgdailywereidentifiedasresponders(definedasadecrease ≥50%frombaseline).At

twoyears78.7%(p=0.002)and65.6%ofpatientswereidentifiedasrespondersinthe150mgmonthlyand2.5mg

dailyarmsrespectively.

BasedontheresultsofstudyBM16549,ibandronicacid150mgoncemonthlyisexpectedtobeatleastaseffectivein

preventingfracturesasibandronicacid2.5mgdaily.

Ibandronicacid2.5mgdaily

Intheinitialthree-year,randomised,double-blind,placebo-controlled,fracturestudy(MF4411),astatistically

significantandmedicallyrelevantdecreaseintheincidenceofnewradiographicmorphometricandclinicalvertebral

fractureswasdemonstrated(table4).Inthisstudy,ibandronicacidwasevaluatedatoraldosesof2.5mgdailyand20

mgintermittentlyasanexploratoryregimen.Ibandronicacidwastaken60minutesbeforethefirstfoodordrinkofthe

day(post-dosefastingperiod).Thestudyenrolledwomenaged55to80years,whowereatleast5years

postmenopausal,whohadaBMDatlumbarspineof2to5SDbelowthepremenopausalmean(T-score)inatleastone

vertebra[L1-L4],andwhohadonetofourprevalentvertebralfractures.Allpatientsreceived500mgcalciumand400

IUvitaminDdaily.Efficacywasevaluatedin2,928patients.Ibandronicacid2.5mgadministereddaily,showeda

statisticallysignificantandmedicallyrelevantreductionintheincidenceofnewvertebralfractures.Thisregimen

reducedtheoccurrenceofnewradiographicvertebralfracturesby62%(p=0.0001)overthethreeyeardurationofthe

study.Arelativeriskreductionof61%wasobservedafter2years(p=0.0006).Nostatisticallysignificantdifference

wasattainedafter1yearoftreatment(p=0.056).Theanti-fractureeffectwasconsistentoverthedurationofthestudy.

changesfrom

baseline%[95%CI] 2.5mgdaily

(N=318) 150mgonce

monthly

(N=320) 2.5mgdaily

(N=294) 150mgonce

monthly

(N=291)

LumbarspineL2-L4

3.9[3.4,4.3] 4.9[4.4,5.3] 5.0[4.4,5.5] 6.6[6.0,7.1]

TotalhipBMD 2.0[1.7,2.3] 3.1[2.8,3.4] 2.5[2.1,2.9] 4.2[3.8,4.5]

FemoralneckBMD 1.7[1.3,2.1] 2.2[1.9,2.6] 1.9[1.4,2.4] 3.1[2.7,3.6]

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Theincidenceofclinicalvertebralfractureswasalsosignificantlyreducedby49%(p=0.011).Thestrongeffecton

vertebralfractureswasfurthermorereflectedbyastatisticallysignificantreductionofheightlosscomparedtoplacebo

(p<0.0001).

Table3:Resultsfrom3yearsfracturestudyMF4411(%,95%CI)

Thetreatmenteffectofibandronicacidwasfurtherassessedinananalysisofthesubpopulationofpatientswhoat

baselinehadalumbarspineBMDT-scorebelow–2.5.Thevertebralfractureriskreductionwasveryconsistentwith

thatseenintheoverallpopulation.

Table4:Resultsfrom3yearsfracturestudyMF4411(%,95%CI)forpatientswithlumbarspineBMDT-scorebelow

–2.5atbaseline

IntheoverallpatientpopulationofthestudyMF4411,noreductionwasobservedfornon-vertebralfractures,however

dailyibandronateappearedtobeeffectiveinahigh-risksubpopulation(femoralneckBMDT-score<-3.0),wherea

non-vertebralfractureriskreductionof69%wasobserved.

Dailytreatmentwith2.5mgresultedinprogressiveincreasesinBMDatvertebralandnonvertebralsitesofthe

skeleton.

Three-yearlumbarspineBMDincreasecomparedtoplacebowas5.3%and6.5%comparedtobaseline.Increasesat

Placebo

(N=974) Ibandronicacid2.5mgdaily

(N=977)

RelativeRiskReductionNew

morphometricvertebral

fractures 62%(40.9,75.1)

Incidenceofnewmorphometric

vertebralfractures 9.56%(7.5,11.7) 4.68%(3.2,6.2)

Relativeriskreductionof

clinicalvertebralfracture 49%

(14.03,69.49)

Incidenceofclinicalvertebral

fracture 5.33%

(3.73,6.92) 2.75%

(1.61,3.89)

BMD–meanchangerelativeto

baselinelumbarspineatyear3 1.26%(0.8,1.7) 6.54%(6.1,7.0)

BMD–meanchangerelativeto

baselinetotalhipatyear3 -0.69%

(-1.0,-0.4) 3.36%

(3.0,3.7)

Placebo

(N=587) Ibandronicacid2.5mgdaily

(N=575)

RelativeRiskReduction

Newmorphometricvertebral

fractures 59%(34.5,74.3)

Incidenceofnewmorphometric

vertebralfractures 12.54%(9.53,15.55) 5.36%(3.31,7.41)

Relativeriskreductionof

clinical

vertebralfracture 50%(9.49,71.91)

Incidenceofclinicalvertebral

fracture 6.97%(4.67,9.27) 3.57%(1.89,5.24)

BMD–meanchangerelativeto

baselinelumbarspineatyear3 1.13%(0.6,1.7) 7.01%(6.5,7.6)

BMD–meanchangerelativeto

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Biochemicalmarkersofboneturnover(suchasurinaryCTXandserumOsteocalcin)showedtheexpectedpatternof

suppressiontopremenopausallevelsandreachedmaximumsuppressionwithinaperiodof3-6months.

Aclinicallymeaningfulreductionof50%ofbiochemicalmarkersofboneresorptionwasobservedasearlyasone

monthafterstartoftreatmentwithibandronicacid2.5mg.

Followingtreatmentdiscontinuation,thereisareversiontothepathologicalpre-treatmentratesofelevatedbone

resorptionassociatedwithpostmenopausalosteoporosis.

Thehistologicalanalysisofbonebiopsiesaftertwoandthreeyearsoftreatmentofpostmenopausalwomenshowed

boneofnormalqualityandnoindicationofamineralizationdefect.

5.2Pharmacokineticproperties

Theprimarypharmacologicaleffectsofibandronicacidonbonearenotdirectlyrelatedtoactualplasma

concentrations,asdemonstratedbyvariousstudiesinanimalsandhumans.

Absorption

Theabsorptionofibandronicacidintheuppergastrointestinaltractisrapidafteroraladministrationandplasma

concentrationsincreaseinadose-proportionalmannerupto50mgoralintake,withgreaterthandose-proportional

increasesseenabovethisdose.Maximumobservedplasmaconcentrationswerereachedwithin0.5to2hours(median

1hour)inthefastedstateandabsolutebioavailabilitywasabout0.6%.Theextentofabsorptionisimpairedwhen

takentogetherwithfoodorbeverages(otherthanplainwater).Bioavailabilityisreducedbyabout90%when

ibandronicacidisadministeredwithastandardbreakfastincomparisonwithbioavailabilityseeninfastedsubjects.

Thereisnomeaningfulreductioninbioavailabilityprovidedibandronicacidistaken60minutesbeforethefirstfoodof

theday.BothbioavailabilityandBMDgainsarereducedwhenfoodorbeverageistakenlessthan60minutesafter

ibandronicacidisingested.

Distribution

Afterinitialsystemicexposure,ibandronicacidrapidlybindstoboneorisexcretedintourine.Inhumans,theapparent

terminalvolumeofdistributionisatleast90landtheamountofdosereachingtheboneisestimatedtobe40-50%of

thecirculatingdose.Proteinbindinginhumanplasmaisapproximately85%-87%(determinedinvitroattherapeutic

concentrations),andthusthereisalowpotentialforinteractionwithothermedicinalproductsduetodisplacement.

Metabolism

Thereisnoevidencethatibandronicacidismetabolisedinanimalsorhumans.

Elimination

Theabsorbedfractionofibandronicacidisremovedfromthecirculationviaboneabsorption(estimatedtobe40-50%

inpostmenopausalwomen)andtheremainderiseliminatedunchangedbythekidney.Theunabsorbedfractionof

ibandronicacidiseliminatedunchangedinthefaeces.

Therangeofobservedapparenthalf-livesisbroad,theapparentterminalhalf-lifeisgenerallyintherangeof10-72

hours.Asthevaluescalculatedarelargelyafunctionofthedurationofstudy,thedoseused,andassaysensitivity,the

trueterminalhalf-lifeislikelytobesubstantiallylonger,incommonwithotherbisphosphonates.

Earlyplasmalevelsfallquicklyreaching10%ofpeakvalueswithin3and8hoursafterintravenousororal

administrationrespectively.

Totalclearanceofibandronicacidislowwithaveragevaluesintherange84-160ml/min.Renalclearance(about60

mL/mininhealthypostmenopausalfemales)accountsfor50-60%oftotalclearanceandisrelatedtocreatinine

clearance.Thedifferencebetweentheapparenttotalandrenalclearancesisconsideredtoreflecttheuptakebybone.

Pharmacokineticsinspecialclinicalsituations

Gender

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Race

Thereisnoevidenceforanyclinicallyrelevantinter-ethnicdifferencesbetweenAsiansandCaucasiansinibandronic

aciddisposition.TherearefewdataavailableonpatientsofAfricanorigin.

Patientswithrenalimpairment

Renalclearanceofibandronicacidinpatientswithvariousdegreesofrenalimpairmentislinearlyrelatedtocreatinine

clearance.

Nodoseadjustmentisnecessaryforpatientswithmildormoderaterenalimpairment(CLcrequalorgreaterthan30

ml/min),asshowninstudyBM16549wherethemajorityofpatientshadmildtomoderaterenalimpairment.

Subjectswithsevererenalfailure(CLcrlessthan30ml/min)receivingdailyoraladministrationof10mgibandronic

acidfor21days,had2-3foldhigherplasmaconcentrationsthansubjectswithnormalrenalfunctionandtotalclearance

ofibandronicacidwas44ml/min.Afterintravenousadministrationof0.5mg,total,renal,andnon-renalclearances

decreasedby67%,77%and50%,respectively,insubjectswithsevererenalfailurebuttherewasnoreductionin

tolerabilityassociatedwiththeincreaseinexposure.Duetothelimitedclinicalexperience,Bonefurbitisnot

recommendedinpatientswithsevererenalimpairment(seesection4.2andsection4.4).Thepharmacokineticsof

ibandronicacidwasnotassessedinpatientswithend-stagerenaldiseasemanagedbyotherthanhemodialysis.The

pharmacokineticsofibandronicacidinthesepatientsisunknown,andibandronicacidshouldnotbeusedunderthese

circumstances.

Patientswithhepaticimpairment

Therearenopharmacokineticdataforibandronicacidinpatientswhohavehepaticimpairment.Theliverhasno

significantroleintheclearanceofibandronicacidwhichisnotmetabolisedbutisclearedbyrenalexcretionandby

uptakeintobone.Thereforedoseadjustmentisnotnecessaryinpatientswithhepaticimpairment.

ElderlyPopulation

Inamultivariateanalysis,agewasnotfoundtobeanindependentfactorofanyofthepharmacokineticparameters

studied.Asrenalfunctiondecreaseswithagethisistheonlyfactortotakeintoconsideration(seerenalimpairment

section).

PaediatricPopulation

TherearenodataontheuseofBonefurbitintheseagegroups.

5.3Preclinicalsafetydata

Toxiceffects,e.gsignsofrenaldamage,wereobservedindogsonlyatexposuresconsideredsufficientlyinexcessof

themaximumhumanexposureindicatinglittlerelevancetoclinicaluse.

Mutagenicity/Carcinogenicity:

Noindicationofcarcinogenicpotentialwasobserved.Testsforgenotoxicityrevealednoevidenceofgeneticactivity

foribandronicacid.

Reproductivetoxicity:

Therewasnoevidenceforadirectfoetaltoxicorteratogeniceffectofibandronicacidinorallytreatedratsandrabbits

andtherewerenoadverseeffectsonthedevelopmentinF

offspringinratsatanextrapolatedexposureofatleast35

timesabovehumanexposure.Adverseeffectsofibandronicacidinreproductivetoxicitystudiesintheratwerethose

observedwithbisphosphonatesasaclass.Theyincludeadecreasednumberofimplantationsites,interferencewith

naturaldelivery(dystocia),andanincreaseinvisceralvariations(renalpelvisuretersyndrome)andteethabnormalities

inF1offspringinrats.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore

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Cellulosemicrocrystalline

Croscarmellosesodium

Magnesiumstearate

Silicacolloidalanhydrous

Tabletcoat

Hydroxypropylcellulose

Titaniumdioxide(E171)

Macrogol6000

6.2Incompatibilities

Notapplicable.

6.3ShelfLife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Bonefurbit150mgfilm-coatedtabletsaresuppliedinblisters(Aluminium/Aluminium)containing1or3tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

LaboratoriosLICONSA,S.A.

GranVìaCarlosIII,98,7thfloor

08028Barcelona

Spain

8MARKETINGAUTHORISATIONNUMBER

PA1239/12/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12thNovember2010

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