ACTONEL PLUS

Main information

  • Trade name:
  • ACTONEL PLUS
  • Dosage:
  • 35/ 1000/ 88 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACTONEL PLUS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1328/090/001
  • Authorization date:
  • 17-04-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ActonelPlusCa&D35mg+1000mg/880IUfilm-coatedtablets+effervescentgranules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains35mgrisedronatesodium,(equivalentto32.5mgrisedronicacid).

Eachsachetofeffervescentgranulescontains2500mgcalciumcarbonateequivalentto1000mgcalciumand22

micrograms(880IU)colecalciferol(vitaminD

Excipients:Eachfilm-coatedtabletcontainslactose.Eachsachetofeffervescentgranulescontainspotassium(163mg),

sucrose,soya-beanoilandsorbitol.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet

Oval,light-orange,film-coatedtabletwithRSNononesideand35mgontheother.

Effervescentgranules

Calciumcarbonate/colecalciferol,whiteeffervescentgranules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpostmenopausalosteoporosis,toreducetheriskofvertebralfractures.

Treatmentofestablishedpostmenopausalosteoporosis,toreducetheriskofhipfractures(seesection5.1).

ActonelPlusCa&DisonlyintendedforuseinassessedpatientsforwhomtheamountofcalciumandvitaminD3

includedisconsideredtoprovideadequatesupplementation.

4.2Posologyandmethodofadministration

AweeklyunitofActonelPlusCa&Dconsistsof1Actonel35mgfilm-coatedtabletand6calcium/vitaminD3

sachetsinabox.

Therecommendeddoseinadultsis1Actonel35mgtabletonthefirstdayfollowedonthenextdayby1

calcium/vitaminD3sachetdailyfor6days.This7-daysequenceisthenrepeatedeachweekstartingwithActonel35

mgtablet.

Actonel35mg(light-orangetablet):

TheActonel35mgtabletshouldbetakenorallyonthesamedayeachweek.

Theabsorptionofrisedronatesodiumisaffectedbyfood,thustoensureadequateabsorption,patientsshouldtakethe

Actonel35mgtablet

Beforebreakfast:atleast30minutesbeforethefirstfood,othermedicinalproductordrink(otherthanplain

water)oftheday.

Thetabletmustbeswallowedwholeandnotsuckedorchewed.ToaiddeliveryofthetablettothestomachtheActonel

35mgtabletistobetakenwhileinanuprightpositionwithaglassofplainwater(>120ml).Patientsshouldnotlie

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Calcium/vitaminD3(sachet):

Calcium/vitaminD3sachetshouldbetakeneachdayfor6daysperweekstartingonthedayaftertheActonel35mg

tabletistaken.Thecontentsofthesachetshouldbepouredintoaglassofplainwater,stirredanddrunkimmediately

oncethefizzinghassubsided.

IncasetheActonel35mgtabletdoseismissed,patientsshouldbeinstructedthattheActonel35mgtabletshouldbe

takenonthenextdayinthemorningaccordingtothedosinginstructions.Inthisparticularinstance,patientsshould

thentaketheircalcium/vitaminD3sachetonthefollowingday.Patientsshouldbeinstructedthattheyshouldnever

takethetabletandthesachetthesameday.

Ifthecalcium/vitaminD3sachetdoseismissed,thepatientshouldbeinstructedtocontinuetakingonesacheteachday

beginningonthedaythemisseddoseisremembered.Patientshouldbeinstructedthattheyshouldnottaketwosachets

onthesameday.Anyremainingcalcium/vitaminD3sachetattheendoftheweeklycycleshouldbediscarded.

Theoptimaldurationofbisphosphonatetreatmentforosteoporosishasnotbeenestablished.Theneedforcontinued

treatmentshouldbere-evaluatedperiodicallybasedonthebenefitsandpotentialrisksofActonelPlusCa&D35mg+

1000mg/880IUfilm-coatedtablets+effervescentgranulesonanindividualpatientbasis,particularlyafter5ormore

yearsofuse.

Elderly:Nodosageadjustmentisnecessarysincebioavailability,distributionandeliminationweresimilarinelderly

>60yearsofage)comparedtoyoungersubjects.Thishasalsobeenshownintheveryelderly,75yearsoldandabove

inpostmenopausalpopulation.

RenalImpairment:Nodosageadjustmentisrequiredforthosepatientswithmildtomoderaterenalimpairment.The

useofrisedronatesodiumandcalcium/vitaminD3iscontraindicatedinpatientswithsevererenalimpairment

(creatinineclearancelowerthan30ml/min)(seesections4.3and5.2).

Paediatricpopulation:Risedronatesodiumisnotrecommendedforuseinchildrenbelowage18duetoinsufficientdata

onsafetyandefficacy(alsoseesection5.1).

4.3Contraindications

Hypersensitivitytorisedronatesodium,calciumcarbonate,colecalciferolortoanyoftheexcipients(inparticularsoya-

beanoil).

Hypocalcaemia(seesection4.4)

Hypercalcaemia.

Hypercalciuria

Diseasesand/orconditions(suchasprolongedimmobilization)associatedwithhypercalcaemiaand/orhypercalciuria

Nephrolithiasis

Pregnancyandlactation.

Severerenalimpairment(creatinineclearance<30ml/min).

HypervitaminosisD

4.4Specialwarningsandprecautionsforuse

Risedronatesodium:

Foods,drinks(otherthanplainwater)andmedicinalproductscontainingpolyvalentcations(suchascalcium,

magnesium,ironandaluminium)mayinterferewiththeabsorptionofrisedronatesodiumandshouldnotbetakenat

thesametime(seesection4.5).Thereforetherisedronatesodiumtablet(light-orangetablet)shouldbetakenatleast30

minutesbeforethefirstfood,othermedicinalproductordrinkoftheday(seesection4.2).

Efficacyofbisphosphonatesinthetreatmentofpostmenopausalosteoporosisisrelatedtothepresenceoflowbone

mineraldensity(BMD)[T-scoreathiporlumbarspine 2.5standarddeviations(SD)]and/orprevalentfracture.

Highageorclinicalriskfactorsforfracturealonearenotsufficientreasonstoinitiatetreatmentofosteoporosiswitha

bisphosphonate.Theevidencetosupportefficacyofbisphosphonatesincludingrisedronatesodiuminveryelderly

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Bisphosphonateshavebeenassociatedwithoesophagitis,gastritis,oesophagealulcerationsandgastroduodenal

ulcerations.Thus,cautionshouldbeused:

Inpatientswhohaveahistoryofoesophagealdisorderswhichdelayoesophagealtransitoremptyinge.g.

strictureorachalasia.

Inpatientswhoareunabletostayintheuprightpositionforatleast30minutesaftertakingthetablet.

Ifrisedronateisgiventopatientswithactiveorrecentoesophagealoruppergastrointestinalproblems.

Prescribersshouldemphasisetopatientstheimportanceofpayingattentiontothedosinginstructionsandbealertto

anysignsandsymptomsofpossibleoesophagealreaction.Thepatientsshouldbeinstructedtoseektimelymedical

attentioniftheydevelopsymptomsofoesophagealirritationsuchasdysphagia,painonswallowing,retrosternalpain

ornew/worsenedheartburn.

HypocalcaemiashouldbetreatedbeforestartingActonelPlusCa&Dtherapy.Otherdisturbancesofboneandmineral

metabolism(i.e.parathyroiddysfunction,hypovitaminosisD)shouldbetreatedatthetimeofstartingActonelPlusCa

&Dtherapy.

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.Clinicaljudgmentofthetreatingphysicianshouldguidethemanagement

planofeachpatientbasedonindividualbenefit/riskassessment.

Atypicalfracturesofthefemur

Atypicalsubtrochantericanddiaphysealfemoralfractureshavebeenreportedwithbisphosphonatetherapy,primarily

inpatientsreceivinglong-termtreatmentforosteoporosis.Thesetransverseorshortoblique,fracturescanoccur

anywherealongthefemurfromjustbelowthelessertrochantertojustabovethesupracondylarflare.Thesefractures

occurafterminimalornotraumaandsomepatientsexperiencethighorgroinpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fracturesareoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureshasalsobeenreported.Discontinuationofbisphosphonate

therapyinpatientssuspectedtohaveanatypicalfemurfractureshouldbeconsideredpendingevaluationofthepatient,

basedonanindividualbenefitriskassessment.

Duringbisphosphonatetreatmentpatientsshouldbeadvisedtoreportanythigh,hiporgroinpainandanypatient

presentingwithsuchsymptomsshouldbeevaluatedforanincompletefemurfracture.

Inpatientswithmildtomoderaterenalimpairmentorahistoryofabsorptiveorrenalhypercalciuria,nephrocalcinosis,

kidneystoneformation,orhypophosphataemia,renalfunction,serumandurinarycalciumandphosphateshouldbe

monitoredregularly.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

Calciumcarbonate/vitaminD3:

VitaminD3shouldbeusedwithcautioninpatientswithimpairmentofrenalfunctionandtheeffectoncalciumand

phosphatelevelsshouldbemonitored.Theriskofsofttissuecalcificationshouldbetakenintoaccount.Inpatientswith

severerenalinsufficiency,vitaminDintheformofcolecalciferolisnotmetabolisednormallyandanotherformof

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Duringlong-termtreatment,serumandurinarycalciumlevelsshouldbefollowedandrenalfunctionshouldbe

monitoredthroughmeasurementofserumcreatinine.Monitoringisespeciallyimportantinelderlypatientson

concomitanttreatmentwithcardiacglycosidesordiuretics(seesection4.5)andinpatientswithahightendencyto

calculusformation.Treatmentmustbereducedorsuspendedifurinarycalciumexceeds7.5mmol/24hour(300mg/24

hour).Incaseofhypercalcaemiaorsignsofimpairedrenalfunction,treatmentwithcalcium/vitaminD3sachetsshould

bediscontinued.

ThedoseofvitaminD3inthesachetsshouldbeconsideredwhenprescribingotherdrugscontainingvitaminD.

AdditionaldosesofcalciumorvitaminDshouldbetakenunderclosemedicalsupervision.Insuchcasesitisnecessary

tomonitorserumcalciumlevelsandurinarycalciumexcretionfrequently.

Calcium/vitaminD3sachetsshouldbeusedwithcautioninpatientssufferingfromsarcoidosisbecauseoftheriskof

increasedmetabolismofvitaminDtoitsactivemetabolite.Inthesepatients,serumcalciumlevelsandurinarycalcium

excretionmustbemonitored.

Calcium/vitaminD3sachetsshouldbeusedwithcautioninimmobilisedpatientswithosteoporosisduetotheincreased

riskofhypercalcaemia.Thecalcium/vitaminD3treatmentmightbediscontinuedinprolongedimmobilizationand

shouldonlyberesumedoncethepatientbecomesmobileagain.

Thismedicinalproductcontainssorbitolandsucrose.Patientswithrarehereditaryproblemsoffructoseintolerance,

glucose-galactosemalabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Risedronatesodium:

Noformalinteractionstudieshavebeenperformedwithrisedronatesodium,howevernoclinicallyrelevantinteractions

withothermedicinalproductswerefoundduringclinicaltrials.IntherisedronatesodiumPhaseIIIosteoporosisstudies

withdailydosing,acetylsalicylicacidornon-steroidalanti-inflammatorydrug(NSAID)usewasreportedby33%and

45%ofpatientsrespectively.InthePhaseIIIonceaweekstudy,acetylsalicylicacidorNSAIDusewasreportedby

57%and40%ofpatientsrespectively.AmongregularacetylsalicylicacidorNSAIDusers(3ormoredaysperweek)

theincidenceofuppergastrointestinaladverseeventsinrisedronatesodiumtreatedpatientswassimilartothatin

controlpatients.

Ifconsideredappropriaterisedronatesodiummaybeusedconcomitantlywithoestrogensupplementation.

Concomitantingestionofmedicationscontainingpolyvalentcations(e.g.calcium,magnesium,ironandaluminium)

willinterferewiththeabsorptionofrisedronatesodium(seesection4.4).

Risedronatesodiumisnotsystemicallymetabolised,doesnotinducecytochromeP450enzymes,andhaslowprotein

binding.

Calciumcarbonate/vitaminD3:

Thiazidediureticsreducetheurinaryexcretionofcalcium.Duetoincreasedriskofhypercalcemiaserumcalcium

shouldberegularlymonitoredduringconcomitantuseofthiazidediuretics.

Systemiccorticosteroidsreducecalciumabsorption.Duringconcomitantuse,itmaybenecessarytoincreasethedose

ofcalcium.

Calciumcarbonatemayinterferewiththeabsorptionofconcomitantadministeredtetracyclinepreparations.Forthis

reason,tetracyclinepreparationsshouldbeadministeredatleasttwohoursbeforeorfourtosixhoursafteroralintake

ofcalciumcarbonate/vitaminD3.

Hypercalcaemiamayincreasethetoxicityofdigitalisandothercardiacglycosides(riskofdysrhythmia)during

treatmentwithcalciumcombinedwithvitaminD3.Suchpatientsshouldbemonitoredwithregardtoelectrocardiogram

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Ifsodiumfluorideisusedconcomitantly,thispreparationshouldbeadministeredatleastthreehoursbeforeintakeof

calciumcarbonate/vitaminD3sincegastrointestinalabsorptionmaybereduced.

Oxalicacid(foundinspinachandrhubarb)andphyticacid(foundinwholecereals)mayinhibitcalciumabsorption

throughformationofinsolublecompoundswithcalciumions.Thepatientshouldnottakecalciumproductswithintwo

hoursofeatingfoodswithhighconcentrationofoxalicacidandphyticacid.

Simultaneoustreatmentwithionexchangeresinssuchascholestyramineorlaxativessuchasparaffinoilmayreduce

thegastrointestinalabsorptionofvitaminD.

4.6Fertility,pregnancyandlactation

Thismedicinalproductiscontraindicatedduringpregnancyandlactation(seesection4.3).

Risedronatesodium:

Therearenoadequatedatafromuseofrisedronatesodiuminpregnantwomen.

Studiesinanimalshaveshownreproductivetoxicity(seesection5.3).Thepotentialrisktohumansisunknown.Studies

inanimalsindicatethatasmallamountofrisedronatesodiumpassintobreastmilk.Risedronatesodiummustnotbe

usedduringpregnancyorbybreast-feedingwomen.

Calciumcarbonate/vitaminD3:

Duringpregnancythedailyintakeshouldnotexceed1500mgcalciumand600IUcolecalciferol(15µgvitaminD3).

TherearenoindicationsthatvitaminDattherapeuticdosesisteratogenicinhumans.Studiesinanimalshaveshown

reproductivetoxicitywithhighdosesofvitaminD.Inpregnantwomen,overdosesofcalciumandvitaminDshouldbe

avoidedaspermanenthypercalcaemiahasbeenrelatedtoadverseeffectsonthedevelopingfoetus.Calciumand

vitaminD3passintobreastmilk.Calciumcarbonate2500mg/vitaminD3880IUdosegranulesmustnotbeused

duringpregnancyandlactation.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

Risedronatesodium:

RisedronatesodiumhasbeenstudiedinphaseIIIclinicaltrialsinvolvingmorethan15,000patients.Themajorityof

undesirableeffectsobservedinclinicaltrialsweremildtomoderateinseverityandusuallydidnotrequirecessationof

therapy.

AdverseexperiencesreportedinphaseIIIclinicaltrialsinpostmenopausalwomenwithosteoporosistreatedforupto

36monthswithrisedronatesodium5mg/day(n=5020)orplacebo(n=5048)andconsideredpossiblyorprobablyrelated

torisedronatesodiumarelistedbelowusingthefollowingconvention(incidencesversusplaceboareshownin

brackets):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).

Nervoussystemdisorders:

Common:headache(1.8%vs.1.4%)

Eyedisorders:

Uncommon:iritis*

Gastrointestinaldisorders:

Common:constipation(5.0%vs.4.8%),dyspepsia(4.5%vs.4.1%),nausea(4.3%vs.4.0%),abdominalpain(3.5%vs.

3.3%),diarrhoea(3.0%vs.2.7%)

Uncommon:gastritis(0.9%vs.0.7%),oesophagitis(0.9%vs.0.9%),dysphagia(0.4%vs.0.2%),duodenitis(0.2%vs.

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Rare:glossitis(<0.1%vs.0.1%),oesophagealstricture(<0.1%vs.0.0%),

Musculoskeletalandconnectivetissuesdisorders:

Common:musculoskeletalpain(2.1%vs.1.9%)

Investigations:

Rare:abnormalliverfunctiontests*

*NorelevantincidencesfromPhaseIIIosteoporosisstudies;frequencybasedonadverseevent/laboratory/rechallenge

findingsinearlierclinicaltrials.

Inaone-year,double-blind,multicentrestudycomparingrisedronate5mgdaily(n=480)andrisedronatesodium35

mgweekly(n=485)inpostmenopausalwomenwithosteoporosis,theoverallsafetyandtolerabilityprofileswere

similar.Thefollowingadditionaladverseexperiencesconsideredpossiblyorprobablydrugrelatedbyinvestigators

havebeenreported(incidencegreaterinrisedronate35mgthaninrisedronatesodium5mggroup):gastrointestinal

disorder(1.6%vs.1.0%)andpain(1.2%vs.0.8%).

Laboratoryfindings:Early,transient,asymptomaticandmilddecreasesinserumcalciumandphosphatelevelshave

beenobservedinsomepatients.

Thefollowingadditionaladversereactionshavebeenreportedduringpost-marketinguse(frequencyunknown):

Eyedisorders:

iritis,uveitis

Muskuloskeletalandconnectivetissuesdisorders:

osteonecrosisofthejaw

Skinandsubcutaneoustissuedisorders:

hypersensitivityandskinreactions,includingangioedema,generalisedrash,urticariaandbullousskinreactions,some

severeincludingisolatedreportsofStevens-Johnsonsyndrome,andtoxicepidermalnecrolysisandleukocytoclastic

vasculitis.

hairloss.

Immunesystemdisorders:

anaphylacticreaction

Hepatobiliarydisorders:

serioushepaticdisorders.Inmostofthereportedcasesthepatientswerealsotreatedwithotherproductsknownto

causehepaticdisorders.

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyrare):

Atypicalsubtrochantericanddiaphysealfemoralfractures(bisphosphonateclassadversereaction)

Calciumcarbonate/vitaminD3

Adversereactionsarelistedbelow,bysystemorganclassandfrequencyfollowingconvention: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).

Metabolismandnutritiondisorders

Uncommon:Hypercalcaemiaandhypercalciuria.

Gastrointestinaldisorders

Rare:Constipation,flatulence,nausea,abdominalpainanddiarrhoea.

Skinandsubcutaneousdisorders

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4.9Overdose

Risedronatesodium:

Nospecificinformationisavailableonthetreatmentofacuteoverdosewithrisedronatesodium.

Decreasesinserumcalciumfollowingsubstantialoverdosemaybeexpected.

Signsandsymptomsofhypocalcaemiamayalsooccurinsomeofthesepatients.

Milkorantacidscontainingmagnesium,calciumoraluminiumshouldbegiventobindrisedronatesodiumandreduce

absorptionofrisedronatesodium.Incasesofsubstantialoverdose,gastriclavagemaybeconsideredtoremove

unabsorbedrisedronatesodium.

Calciumcarbonate/vitaminD3:

Overdosecanleadtohypervitaminosis,hypercalciuraandhypercalcaemia.Symptomsofhypercalcaemiamayinclude

anorexia,thirst,nausea,vomiting,constipation,abdominalpain,muscleweakness,fatigue,mentaldisturbances,

polydipsia,polyuria,bonepain,nephrocalcinosis,renalcalculiandinseverecases,cardiacarrhythmias.Extreme

hypercalcaemiamayresultincomaanddeath.Persistentlyhighcalciumlevelsmayleadtoirreversiblerenaldamage

andsofttissuecalcification.

Treatmentofhypercalcaemia:Thetreatmentwithcalciummustbediscontinued.

Treatmentwiththiazidediuretics,lithium,vitaminA,vitaminD3andcardiacglycosidesmustalsobediscontinued.

Emptyingofthestomachinpatientswithimpairedconsciousness.Rehydration,and,accordingtoseverity,isolatedor

combinedtreatmentwithloopdiuretics,bisphosphonates,calcitoninandcorticosteroids.Serumelectrolytes,renal

functionanddiuresismustbemonitored.Inseverecases,ECGandcentralvenouspressureshouldbefollowed.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:Bisphosphonates,combinations,

ATCCode:M05BB04.

Risedronatesodium:

Risedronatesodiumisapyridinylbisphosphonatethatbindstobonehydroxyapatiteandinhibitsosteoclast-mediated

boneresorption.Theboneturnoverisreducedwhiletheosteoblastactivityandbonemineralisationispreserved.In

preclinicalstudiesrisedronatesodiumdemonstratedpotentantiosteoclastandantiresorptiveactivity,anddose

dependentlyincreasedbonemassandbiomechanicalskeletalstrength.Theactivityofrisedronatesodiumwas

confirmedbymeasuringbiochemicalmarkersforboneturnoverduringpharmacodynamicandclinicalstudies.

Decreasesinbiochemicalmarkersofboneturnoverwereobservedwithin1monthandreachedamaximumin3-6

months.

Decreasesinbiochemicalmarkersofboneturnoverweresimilarwithrisedronatesodium35mgweeklyand

risedronatesodium5mgdailyat12months.

TreatmentofPostmenopausalOsteoporosis:

Anumberofriskfactorsareassociatedwithpostmenopausalosteoporosisincludinglowbonemass,lowbonemineral

density,earlymenopause,ahistoryofsmokingandafamilyhistoryofosteoporosis.Theclinicalconsequenceof

osteoporosisisfractures.Theriskoffracturesisincreasedwiththenumberofriskfactors.

Basedoneffectsonmeanchangeinlumbarspinebonemineraldensity(BMD),risedronatesodium35mgweekly

(n=485)wasshowntobeequivalenttorisedronatesodium5mgdaily(n=480)inaone-year,double-blind,multicentre

studyofpostmenopausalwomenwithosteoporosis.

Theclinicalprogrammeforrisedronatesodiumadministeredoncedailystudiedtheeffectofrisedronatesodiumonthe

riskofhipandvertebralfracturesandcontainedearlyandlatepostmenopausalwomenwithandwithoutfracture.Daily

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baselinelevelswerelow).Theabsoluteandrelativeriskofnewvertebralandhipfractureswereestimatedbyuseofa

time-to-firsteventanalysis.

Twoplacebo-controlledtrials(n=3661)enrolledpostmenopausalwomenunder85yearswithvertebralfracturesat

baseline.Risedronatesodium5mgdailygivenfor3yearsreducedtheriskofnewvertebralfracturesrelativetothe

controlgroup.Inwomenwithrespectivelyatleast2oratleast1vertebralfractures,therelativeriskreductionwas49%

and41%respectively(incidenceofnewvertebralfractureswithrisedronatesodium18.1%and11.3%,withplacebo

29.0%and16.3%,respectively).Theeffectoftreatmentwasseenasearlyastheendofthefirstyearoftreatment.

Benefitswerealsodemonstratedinwomenwithmultiplefracturesatbaseline.Risedronatesodium5mgdailyalso

reducedtheyearlyheightlosscomparedtothecontrolgroup.

Twofurtherplacebocontrolledtrialsenrolledpostmenopausalwomenabove70yearswithorwithoutvertebral

fracturesatbaseline.Women70-79yearswereenrolledwithfemoralneckBMDT-score<-3SD(manufacturer's

range,i.e.-2.5SDusingNHANESIII)andatleastoneadditionalriskfactor.Women80yearscouldbeenrolledonthe

basisofatleastonenon-skeletalriskfactorforhipfractureorlowbonemineraldensityatthefemoralneck.Statistical

significanceoftheefficacyofrisedronatesodiumversusplaceboisonlyreachedwhenthetwotreatmentgroups2.5mg

and5mgarepooled.Thefollowingresultsareonlybasedona-posteriorianalysisofsubgroupsdefinedbyclinical

practiseandcurrentdefinitionsofosteoporosis:

-InthesubgroupofpatientswithfemoralneckBMDT-score-2.5SD(NHANESIII)andatleastonevertebralfracture

atbaseline,risedronatesodiumgivenfor3yearsreducedtheriskofhipfracturesby46%relativetothecontrolgroup

(incidenceofhipfracturesincombinedrisedronatesodium2.5and5mggroups3.8%,placebo7.4%);

-Datasuggestthatamorelimitedprotectionthanthismaybeobservedintheveryelderly(80years).Thismaybedue

totheincreasingimportanceofnonskeletalfactorsforhipfracturewithincreasingage.Inthesetrials,dataanalysedas

asecondaryendpointindicatedadecreaseintheriskofnewvertebralfracturesinpatientswithlowfemoralneckBMD

withoutvertebralfractureandinpatientswithlowfemoralneckBMDwithorwithoutvertebralfracture.

Risedronatesodium5mgdailygivenfor3yearsincreasedBMDrelativetocontrolatthelumbarspine,femoralneck,

trochanterandwristandmaintainedbonedensityatthemid-shaftradius.

Inaone-yearfollow-upofftherapyafterthreeyearstreatmentwithrisedronatesodium5mgdailytherewasrapid

reversibilityofthesuppressingeffectofrisedronatesodiumonboneturnoverrate.

Bonebiopsysamplesfrompostmenopausalwomentreatedwithrisedronatesodium5mgdailyfor2to3years,

showedanexpectedmoderatedecreaseinboneturnover.Boneformedduringrisedronatesodiumtreatmentwasof

normallamellarstructureandbonemineralisation.Thesedatatogetherwiththedecreasedincidenceofosteoporosis

relatedfracturesatvertebralsitesinwomenwithosteoporosisappeartoindicatenodetrimentaleffectonbonequality.

Endoscopicfindingsfromanumberofpatientswithanumberofmoderatetoseveregastrointestinalcomplaintsin

bothrisedronatesodiumandcontrolpatientsindicatednoevidenceoftreatmentrelatedgastric,duodenalor

oesophagealulcersineithergroup,althoughduodenitiswasuncommonlyobservedintherisedronatesodiumgroup.

Calciumcarbonate/vitaminD3:

Incaseofcalciumdeficiency,oralintakeofcalciumsupplementationsupportstheremineralisationoftheskeleton.

VitaminD3increasestheintestinalabsorptionofcalcium.

AdministrationofcalciumandvitaminD3counteractstheincreaseinparathyroidhormone(PTH)whichiscausedby

calciumdeficiencywhichcausesincreasedboneresorption.

AclinicalstudyofinstitutionalisedpatientssufferingfromvitaminDdeficiencyindicatedthatadailyintakeof

effervescentgranulesof1000mgcalcium/880IUcolecalciferolforsixmonthsnormalisedthevalueofthe25-

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5.2Pharmacokineticproperties

Risedronatesodium:

Absorption:risedronatesodiumabsorptionafteranoraldoseisrelativelyrapid(tmax~1hour)andisindependentof

doseovertherangestudied(singledosestudy,2.5to30mg;multipledosestudies,2.5to5mgdailyandupto50mg

dosedweekly).Meanoralbioavailabilityofthetabletis0.63%andisdecreasedwhenrisedronatesodiumis

administeredwithfood.Bioavailabilitywassimilarinmenandwomen.

Distribution:Themeansteadystatevolumeofdistributionofrisedronatesodiumis6.3l/kginhumans.Plasmaprotein

bindingisabout24%.

Metabolism:Thereisnoevidenceofsystemicmetabolismofrisedronatesodium.

Elimination:Approximatelyhalfoftheabsorbedrisedronatesodiumdoseisexcretedinurinewithin24hours,and85%

ofanintravenousdoseisrecoveredintheurineafter28days.Meanrenalclearanceis105ml/minandmeantotal

clearanceis122ml/min,withthedifferenceprobablyattributedtoclearanceduetoadsorptiontobone.Therenal

clearanceisnotconcentrationdependent,andthereisalinearrelationshipbetweenrenalclearanceandcreatinine

clearance.

Unabsorbedrisedronatesodiumiseliminatedunchangedinfaeces.Afteroraladministrationtheconcentration-time

profileshowsthreeeliminationphaseswithaterminalhalf-lifeof480hours.

SpecialPopulations

Elderly:nodosageadjustmentisnecessary.

Acetylsalicylicacid/NSAIDusers:AmongregularacetylsalicylicacidorNSAIDusers(3ormoredaysperweek)the

incidenceofuppergastrointestinaladverseeventsinrisedronatesodiumtreatedpatientswassimilartothatincontrol

patients.

Calciumcarbonate:

Absorption:Duringdissolutionthecalciumsaltcontainedintheeffervescentgranulesistransformedintocalcium

citrate.Calciumcitrateiswellabsorbed,approximately30%to40%oftheingesteddose.

Distributionandmetabolism:99%ofcalciuminthebodyisconcentratedinthehardstructureofbonesandteeth.The

remaining1%ispresentintheintra-andextracellularfluids.About50%ofthetotalbloodcalciumcontentis

physiologicallyactiveionisedformwithapproximately10%beingcomplexedtocitrate,phosphateorotheranions,the

remaining40%beingboundtoproteins,principallyalbumin.

Elimination:Calciumiseliminatedthroughfaeces,urineandsweat.Renalexcretiondependsonglomerularfiltration

andcalciumtubularreabsorption.

VitaminD3:

Absorption:VitaminDisreadilyabsorbedinthesmallintestine.

Distributionandmetabolism:Colecalciferolanditsmetabolitescirculateinthebloodboundtoaspecificglobulin.

Colecalciferolisconvertedintheliverbyhydroxylationtotheactiveform25-hydroxycolecalciferol.Itisthenfurther

convertedinthekidneysto1,25hydroxycolecalciferol.1,25hydroxycolecalciferolisthemetaboliteresponsiblefor

increasingcalciumabsorption.VitaminDthatisnotmetabolisedisstoredinadiposeandmuscletissues.

Elimination:VitaminDisexcretedinfaecesandurine.

5.3Preclinicalsafetydata

Risedronatesodium:

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enzymeincreaseswithhistologicalchangesinrat.Theclinicalrelevanceoftheseobservationsisunknown.

Testiculartoxicityoccurredinratanddogatexposuresconsideredinexcessofthehumantherapeuticexposure.Dose

relatedincidencesofupperairwayirritationwerefrequentlynotedinrodents.Similareffectshavebeenseenwithother

bisphosphonates.Lowerrespiratorytracteffectswerealsoseeninlongertermstudiesinrodents,buttheclinical

significanceofthesefindingsisunclear.

Inreproductiontoxicitystudiesatexposuresclosetoclinicalexposureossificationchangeswereseeninsternumand/or

skulloffoetusesfromtreatedratsandhypocalcemiaandmortalityinpregnantfemalesallowedtodeliver.

Therewasnoevidenceofteratogenesisat3.2mg/kg/dayinratand10mg/kg/dayinrabbit,althoughdataareonly

availableonasmallnumberofrabbits.Maternaltoxicitypreventedtestingofhigherdoses.Studiesongenotoxicityand

carcinogenesisdidnotshowanyparticularriskforhumans.

Calciumcarbonate/vitaminD3:

Atdosesfarhigherthanthehumantherapeuticrange,teratogenicityhasbeenobservedinanimalstudies(seesection

4.6).Thereisnofurtherinformationofrelevancetothesafetyassessmentinadditiontowhatisstatedinotherpartsof

theSPC.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Film-coatedtablet:

Tabletcore:Lactosemonohydrate

Cellulosemicrocrystalline

CrospovidoneA

Magnesiumstearate

Filmcoating:Hypromellose

Macrogol

Hyprolose

Silicondioxide

Titaniumdioxide(E171)

Ironoxideyellow(E172)

Ironoxidered(E172)

Effervescentgranules:

Citricacidanhydrous

Malicacid

Gluconolactone

Maltodextrin

Sodiumcyclamate

Saccharinsodium

SorbitolE420

MannitolE421

Gluconolactone

Dextrin,acacia

Lemonoils

Limeflavour

Ricestarch

Potassiumcarbonate

All-rac--Tocopherol

Soya-beanoil,hydrogenated

Gelatin

Sucrose

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6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Combinationpackconstitutedofanoutercartonpackcontainingweeklyunit(s)(cartonboxes).

Eachweeklyunitcontains:

ClearPVC/aluminiumfoilblistercontainingonetablet

Sixsachets(laminatedaluminiumpaperfoil)containingeffervescentgranules

Packsizes:

4weeklyunits:4x(1film-coatedtablet+effervescentgranulesin6sachets)

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

B&SHealthcare

Unit4,BradfieldRoad

Ruislip

MiddlesexHA40NU

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1328/90/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:17thApril2009

10DATEOFREVISIONOFTHETEXT

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