ACTONEL PLUS CA & D

Main information

  • Trade name:
  • ACTONEL PLUS CA & D
  • Dosage:
  • 35 + 1000 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACTONEL PLUS CA & D
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1659/041/001
  • Authorization date:
  • 26-08-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ActonelPlusCa&D35mgfilm-coatedtablets+1000mg/880IUEffervescentGranules.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains35mgrisedronatesodium,(equivalentto32.5mgrisedronicacid).

Eachsachetofeffervescentgranulescontains2500mgcalciumcarbonateequivalentto1000mgcalciumand22

micrograms(880IU)colecalciferol(vitaminD

Excipients:Eachfilm-coatedtabletcontainslactose.Eachsachetofeffervescentgranulescontainspotassium(163

mg),sucrose,soya-beanoilandsorbitol.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablets.

ProductimportedfromtheUK:

Risedronatetablets:Oval,light-orange,film-coatedtabletswithRSNononesideand35mgontheother.

Effervescentgranules:Calciumcarbonate/colecalciferol,whiteeffervescentgranules.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpostmenopausalosteoporosis,toreducetheriskofvertebralfractures.

Treatmentofestablishedpostmenopausalosteoporosis,toreducetheriskofhipfractures(seesection5.1).

ActonelPlusCa&DisonlyintendedforuseinassessedpatientsforwhomtheamountofcalciumandvitaminD

includedisconsideredtoprovideadequatesupplementation.

4.2Posologyandmethodofadministration

AweeklyunitofActonelPlusCa&Dconsistsof1Actonel35mgfilm-coatedtabletand6calcium/vitaminD

sachets

inabox.

Therecommendeddoseinadultsis1Actonel35mgtabletonthefirstdayfollowedonthenextdayby1

calcium/vitaminD

sachetdailyfor6days.This7-daysequenceisthenrepeatedeachweekstartingwithActonel35

mgtablet.

Actonel35mg(light-orangetablet):

TheActonel35mgtabletshouldbetakenorallyonthesamedayeachweek.

Theabsorptionofrisedronatesodiumisaffectedbyfood,thustoensureadequateabsorption,patientsshouldtakethe

Actonel35mgtablet

Beforebreakfast:atleast30minutesbeforethefirstfood,othermedicinalproductordrink(otherthanplain

water)oftheday.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 1

Actonel35mgtabletistobetakenwhileinanuprightpositionwithaglassofplainwater>120ml).

Patientsshouldnotliedownfor30minutesaftertakingthetablet(seesection4.4).

Calcium/vitaminD

(sachet):

Calcium/vitaminD

sachetshouldbetakeneachdayfor6daysperweekstartingonthedayaftertheActonel35mg

tabletistaken.Thecontentsofthesachetshouldbepouredintoaglassofplainwater,stirredanddrunkimmediately

oncethefizzinghassubsided.

IncasetheActonel35mgtabletdoseismissed,patientsshouldbeinstructedthattheActonel35mgtabletshouldbe

takenonthenextdayinthemorningaccordingtothedosinginstructions.Inthisparticularinstance,patientsshould

thentaketheircalcium/vitaminD

sachetonthefollowingday.Patientsshouldbeinstructedthattheyshouldnever

takethetabletandthesachetthesameday.

Ifthecalcium/vitaminD

sachetdoseismissed,thepatientshouldbeinstructedtocontinuetakingonesacheteachday

beginningonthedaythemisseddoseisremembered.Patientshouldbeinstructedthattheyshouldnottaketwosachets

onthesameday.Anyremainingcalcium/vitaminD

sachetattheendoftheweeklycycleshouldbediscarded.

Theoptimaldurationofbisphosphonatetreatmentforosteoporosishasnotbeenestablished.Theneedforcontinued

treatmentshouldbere-evaluatedperiodicallybasedonthebenefitsandpotentialrisksofrisedronateonanindividual

patientbasis,particularlyafter5ormoreyearsofuse.

Elderly:Nodosageadjustmentisnecessarysincebioavailability,distributionandeliminationweresimilarinelderly

(>60yearsofage)comparedtoyoungersubjects.Thishasalsobeenshownintheveryelderly,75yearsoldandabove

inpostmenopausalpopulation.

RenalImpairment:Nodosageadjustmentisrequiredforthosepatientswithmildtomoderaterenalimpairment.The

useofrisedronatesodiumandcalcium/vitaminD

iscontraindicatedinpatientswithsevererenalimpairment

(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).

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 2

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

Highageorclinicalriskfactorsforfracturealonearenotsufficientreasonstoinitiatetreatmentofosteoporosiswitha

bisphosphonate.Theevidencetosupportefficacyofbisphosphonatesincludingrisedronatesodiuminveryelderly

women(>80years)islimited(seesection5.1).

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.Thesetransverseorshortobliquefracturescanoccur

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

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 3

Calciumcarbonate/vitaminD

VitaminD

shouldbeusedwithcautioninpatientswithimpairmentofrenalfunctionandtheeffectoncalciumand

phosphatelevelsshouldbemonitored.Theriskofsofttissuecalcificationshouldbetakenintoaccount.Inpatients

withsevererenalinsufficiency,vitaminDintheformofcolecalciferolisnotmetabolisednormallyandanotherformof

vitaminDshouldbeused(seesection4.3)

Duringlong-termtreatment,serumandurinarycalciumlevelsshouldbefollowedandrenalfunctionshouldbe

monitoredthroughmeasurementofserumcreatinine.Monitoringisespeciallyimportantinelderlypatientson

concomitanttreatmentwithcardiacglycosidesordiuretics(seesection4.5)andinpatientswithahightendencyto

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

hour).Incaseofhypercalcaemiaorsignsofimpairedrenalfunction,treatmentwithcalcium/vitaminD

sachetsshould

bediscontinued.

ThedoseofvitaminD

inthesachetsshouldbeconsideredwhenprescribingotherdrugscontainingvitaminD.

AdditionaldosesofcalciumorvitaminDshouldbetakenunderclosemedicalsupervision.Insuchcasesitisnecessary

tomonitorserumcalciumlevelsandurinarycalciumexcretionfrequently.

Calcium/vitaminD

sachetsshouldbeusedwithcautioninpatientssufferingfromsarcoidosisbecauseoftheriskof

increasedmetabolismofvitaminDtoitsactivemetabolite.Inthesepatients,serumcalciumlevelsandurinarycalcium

excretionmustbemonitored.

Calcium/vitaminD

sachetsshouldbeusedwithcautioninimmobilisedpatientswithosteoporosisduetotheincreased

riskofhypercalcaemia.Thecalcium/vitaminD

treatmentmightbediscontinuedinprolonged

immobilizationandshouldonlyberesumedoncethepatientbecomesmobileagain.

Thismedicinalproductcontainssorbitolandsucrose.Patientswithrarehereditaryproblemsoffructoseintolerance,

glucose-galactosemalabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Risedronatesodium:

Noformalinteractionstudieshavebeenperformedwithrisedronatesodium,howevernoclinicallyrelevantinteractions

withothermedicinalproductswerefoundduringclinicaltrials.IntherisedronatesodiumPhaseIIIosteoporosis

studieswithdailydosing,acetylsalicylicacidornon-steroidalanti-inflammatorydrug(NSAID)usewasreportedby

33%and45%ofpatientsrespectively.InthePhaseIIIonceaweekstudy,acetylsalicylicacidorNSAIDusewas

reportedby57%and40%ofpatientsrespectively.AmongregularacetylsalicylicacidorNSAIDusers(3ormore

daysperweek)theincidenceofuppergastrointestinaladverseeventsinrisedronatesodiumtreatedpatientswassimilar

tothatincontrolpatients.

Ifconsideredappropriaterisedronatesodiummaybeusedconcomitantlywithoestrogensupplementation.

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

willinterferewiththeabsorptionofrisedronatesodium(seesection4.4).

Risedronatesodiumisnotsystemicallymetabolised,doesnotinducecytochromeP450enzymes,andhaslowprotein

binding.

Calciumcarbonate/vitaminD:

Thiazidediureticsreducetheurinaryexcretionofcalcium.Duetoincreasedriskofhypercalcemiaserumcalcium

shouldberegularlymonitoredduringconcomitantuseofthiazidediuretics.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 4

ofcalcium.

Calciumcarbonatemayinterferewiththeabsorptionofconcomitantadministeredtetracyclinepreparations.Forthis

reason,tetracyclinepreparationsshouldbeadministeredatleasttwohoursbeforeorfourtosixhoursafteroralintake

ofcalciumcarbonate/vitaminD.

Hypercalcaemiamayincreasethetoxicityofdigitalisandothercardiacglycosides(riskofdysrhythmia)during

treatmentwithcalciumcombinedwithvitaminD.

Suchpatientsshouldbemonitoredwithregardtoelectrocardiogram(ECG)andserumcalciumlevels.

Ifsodiumfluorideisusedconcomitantly,thispreparationshouldbeadministeredatleastthreehoursbeforeintakeof

calciumcarbonate/vitaminDsincegastrointestinalabsorptionmaybereduced.

Oxalicacid(foundinspinachandrhubarb)andphyticacid(foundinwholecereals)mayinhibitcalciumabsorption

throughformationofinsolublecompoundswithcalciumions.Thepatientshouldnottakecalciumproductswithintwo

hoursofeatingfoodswithhighconcentrationofoxalicacidandphyticacid.

Simultaneoustreatmentwithionexchangeresinssuchascholestyramineorlaxativessuchasparaffinoilmayreducethe

gastrointestinalabsorptionofvitaminD.

4.6Fertility,pregnancyandlactation

Thismedicinalproductiscontraindicatedduringpregnancyandlactation(seesection4.3).

Risedronatesodium:

Therearenoadequatedatafromuseofrisedronatesodiuminpregnantwomen.Studiesinanimalshaveshown

reproductivetoxicity(seesection5.3).Thepotentialrisktohumansisunknown.Studiesinanimalsindicatethata

smallamountofrisedronatesodiumpassintobreastmilk.Risedronatesodiummustnotbeusedduringpregnancyor

bybreast-feedingwomen.

Calciumcarbonate/vitaminD

Duringpregnancythedailyintakeshouldnotexceed1500mgcalciumand600IUcolecalciferol(15µgvitaminD

TherearenoindicationsthatvitaminDattherapeuticdosesisteratogenicinhumans.Studiesinanimalshaveshown

reproductivetoxicitywithhighdosesofvitaminD.Inpregnantwomen,overdosesofcalciumandvitaminDshouldbe

avoidedaspermanenthypercalcaemiahasbeenrelatedtoadverseeffectsonthedevelopingfoetus.Calciumand

vitaminD

passintobreastmilk.Calciumcarbonate2500mg/vitaminD

880IUdosegranulesmustnotbeused

duringpregnancyandlactation.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

Risedronatesodium:

RisedronatesodiumhasbeenstudiedinphaseIIIclinicaltrialsinvolvingmorethan15,000patients.

Themajorityofundesirableeffectsobservedinclinicaltrialsweremildtomoderateinseverityandusuallydidnot

requirecessationoftherapy.

AdverseexperiencesreportedinphaseIIIclinicaltrialsinpostmenopausalwomenwithosteoporosistreatedforupto

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

torisedronatesodiumarelistedbelowusingthefollowingconvention(incidencesversusplaceboareshownin

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 5

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.

0.1%),oesophagealulcer(0.2%vs.0.2%)

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.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 6

Atypicalsubtrochantericanddiaphysealfemoralfractures(bisphosphonateclassadversereaction).

Calciumcarbonate/vitaminD

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

Rare:Pruritus,rashandurticaria.

4.9Overdose

Risedronatesodium:

Nospecificinformationisavailableonthetreatmentofacuteoverdosewithrisedronatesodium.

Decreasesinserumcalciumfollowingsubstantialoverdosemaybeexpected.Signsandsymptomsofhypocalcaemia

mayalsooccurinsomeofthesepatients.

Milkorantacidscontainingmagnesium,calciumoraluminiumshouldbegiventobindrisedronatesodiumandreduce

absorptionofrisedronatesodium.Incasesofsubstantialoverdose,gastriclavagemaybeconsideredtoremove

unabsorbedrisedronatesodium.

Calciumcarbonate/vitaminD:

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,vitaminDandcardiacglycosidesmustalsobediscontinued.Emptyingofthestomachinpatients

withimpairedconsciousness.Rehydration,and,accordingtoseverity,isolatedorcombinedtreatmentwithloop

diuretics,bisphosphonates,calcitoninandcorticosteroids.Serumelectrolytes,renalfunctionanddiuresismustbe

monitored.Inseverecases,ECGandcentralvenouspressureshouldbefollowed.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:Bisphosphonates,combinations,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 7

Risedronatesodium:

Risedronatesodiumisapyridinylbisphosphonatethatbindstobonehydroxyapatiteandinhibitsosteoclast-mediated

boneresorption.Theboneturnoverisreducedwhiletheosteoblastactivityandbonemineralisationispreserved.In

preclinicalstudiesrisedronatesodiumdemonstratedpotentanti-osteoclastandantiresorptiveactivity,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.

Dailydosesof2.5mgand5mgwerestudiedandallgroups,includingthecontrolgroups,receivedcalciumand

vitaminD(ifbaselinelevelswerelow).Theabsoluteandrelativeriskofnewvertebralandhipfractureswere

estimatedbyuseofatime-to-firsteventanalysis.

Twoplacebo-controlledtrials(n=3661)enrolledpostmenopausalwomenunder85yearswithvertebralfracturesat

baseline.Risedronatesodium5mgdailygivenfor3yearsreducedtheriskofnewvertebralfracturesrelativetothe

controlgroup.Inwomenwithrespectivelyatleast2oratleast1vertebralfractures,therelativeriskreductionwas

49%and41%respectively(incidenceofnewvertebralfractureswithrisedronatesodium18.1%and11.3%,with

placebo29.0%and16.3%,respectively).Theeffectoftreatmentwasseenasearlyastheendofthefirstyearof

treatment.Benefitswerealsodemonstratedinwomenwithmultiplefracturesatbaseline.Risedronatesodium5

mgdailyalsoreducedtheyearlyheightlosscomparedtothecontrolgroup.

Twofurtherplacebocontrolledtrialsenrolledpostmenopausalwomenabove70yearswithorwithoutvertebral

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

range,i.e.-2.5SDusingNHANESIII)andatleastoneadditionalriskfactor.Women80yearscouldbeenrolled

onthebasisofatleastonenon-skeletalriskfactorforhipfractureorlowbonemineraldensityatthefemoralneck.

Statisticalsignificanceoftheefficacyofrisedronatesodiumversusplaceboisonlyreachedwhenthetwotreatment

groups2.5mgand5mgarepooled.Thefollowingresultsareonlybasedona-posteriorianalysisofsubgroups

definedbyclinicalpractiseandcurrentdefinitionsofosteoporosis:

InthesubgroupofpatientswithfemoralneckBMDT-score-2.5SD(NHANESIII)andatleastonevertebral

fractureatbaseline,risedronatesodiumgivenfor3yearsreducedtheriskofhipfracturesby46%relativeto

thecontrolgroup(incidenceofhipfracturesincombinedrisedronatesodium2.5and5mggroups3.8%,

placebo7.4%);

Datasuggestthatamorelimitedprotectionthanthismaybeobservedintheveryelderly(80years).This

maybeduetotheincreasingimportanceofnon-skeletalfactorsforhipfracturewithincreasingage.

Inthesetrials,dataanalysedasasecondaryendpointindicatedadecreaseintheriskofnewvertebralfracturesin

patientswithlowfemoralneckBMDwithoutvertebralfractureandinpatientswithlowfemoralneckBMDwithor

withoutvertebralfracture.

Risedronatesodium5mgdailygivenfor3yearsincreasedBMDrelativetocontrolatthelumbarspine,femoral

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 8

Inaone-yearfollow-upofftherapyafterthreeyearstreatmentwithrisedronatesodium5mgdailytherewasrapid

reversibilityofthesuppressingeffectofrisedronatesodiumonboneturnoverrate.

Bonebiopsysamplesfrompostmenopausalwomentreatedwithrisedronatesodium5mgdailyfor2to3years,

showedanexpectedmoderatedecreaseinboneturnover.Boneformedduringrisedronatesodiumtreatmentwasof

normallamellarstructureandbonemineralisation.Thesedatatogetherwiththedecreasedincidenceof

osteoporosisrelatedfracturesatvertebralsitesinwomenwithosteoporosisappeartoindicatenodetrimentaleffect

onbonequality.

Endoscopicfindingsfromanumberofpatientswithanumberofmoderatetoseveregastrointestinalcomplaintsin

bothrisedronatesodiumandcontrolpatientsindicatednoevidenceoftreatmentrelatedgastric,duodenalor

oesophagealulcersineithergroup,althoughduodenitiswasuncommonlyobservedintherisedronatesodium

group.

Calciumcarbonate/vitaminD

Incaseofcalciumdeficiency,oralintakeofcalciumsupplementationsupportstheremineralisationoftheskeleton.

VitaminDincreasestheintestinalabsorptionofcalcium.

AdministrationofcalciumandvitaminD

counteractstheincreaseinparathyroidhormone(PTH)whichiscausedby

calciumdeficiencywhichcausesincreasedboneresorption.

AclinicalstudyofinstitutionalisedpatientssufferingfromvitaminDdeficiencyindicatedthatadailyintakeof

effervescentgranulesof1000mgcalcium/880IUcolecalciferolforsixmonthsnormalisedthevalueofthe25-

hydoxylatedmetaboliteofvitaminD

andreducedsecondaryhyperparathyroidism.

Paediatricpopulation:Thesafetyandefficacyofrisedronatesodiumisbeinginvestigatedinanon-goingstudyof

paediatricpatientsaged4tolessthan16yearswithosteogenesisimperfecta.Aftercompletionofitsone-year

randomized,double-blind,placebocontrolledphase,astatisticallysignificantincreaseinlumbarspineBMDinthe

risedronategroupversusplacebogroupwasdemonstrated:howeveranincreasednumberofatleast1new

morphometric(identifiedbyx-ray)vertebralfracturewasfoundintherisedronategroupcomparedtoplacebo.Overall,

resultsdonotsupporttheuseofrisedronatesodiuminpaediatricpatientswithosteogenesisimperfecta.

5.2Pharmacokineticproperties

Risedronatesodium:

Absorption:risedronatesodiumabsorptionafteranoraldoseisrelativelyrapid(t

~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-timeprofileshowsthreeeliminationphaseswithaterminalhalf-lifeof480

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 9

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.

VitaminD

Absorption:VitaminDisreadilyabsorbedinthesmallintestine.

Distributionandmetabolism:Colecalciferolanditsmetabolitescirculateinthebloodboundtoaspecificglobulin.

Colecalciferolisconvertedintheliverbyhydroxylationtotheactiveform25-hydroxycolecalciferol.Itisthenfurther

convertedinthekidneysto1,25hydroxycolecalciferol.1,25hydroxycolecalciferolisthemetaboliteresponsiblefor

increasingcalciumabsorption.VitaminDthatisnotmetabolisedisstoredinadiposeandmuscletissues.

Elimination:VitaminDisexcretedinfaecesandurine.

5.3Preclinicalsafetydata

Risedronatesodium:

Intoxicologicalstudiesinratanddogdosedependentlivertoxiceffectsofrisedronatesodiumwereseen,primarilyas

enzymeincreaseswithhistologicalchangesinrat.Theclinicalrelevanceoftheseobservationsisunknown.Testicular

toxicityoccurredinratanddogatexposuresconsideredinexcessofthehumantherapeuticexposure.Doserelated

incidencesofupperairwayirritationwerefrequentlynotedinrodents.Similareffectshavebeenseenwithother

bisphosphonates.Lowerrespiratorytracteffectswerealsoseeninlongertermstudiesinrodents,buttheclinical

significanceofthesefindingsisunclear.Inreproductiontoxicitystudiesatexposuresclosetoclinicalexposure

ossificationchangeswereseeninsternumand/orskulloffoetusesfromtreatedratsandhypocalcemiaandmortalityin

pregnantfemalesallowedtodeliver.Therewasnoevidenceofteratogenesisat3.2mg/kg/dayinratand10mg/kg/day

inrabbit,althoughdataareonlyavailableonasmallnumberofrabbits.Maternaltoxicitypreventedtestingofhigher

doses.Studiesongenotoxicityandcarcinogenesisdidnotshowanyparticularriskforhumans.

Calciumcarbonate/vitaminD

Atdosesfarhigherthanthehumantherapeuticrange,teratogenicityhasbeenobservedinanimalstudies(seesection

4.6).Thereisnofurtherinformationofrelevancetothesafetyassessmentinadditiontowhatisstatedinotherpartsof

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 10

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

Maizestarch

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 11

6.5Natureandcontentsofcontainer

Combinationpackconstitutedofanoutercartonpackcontainingweeklyunit(s)(cartonboxes)

Eachweeklyunitcontains:

ClearPVC/aluminiumfoilblistercontainingonetablet

Sixsachets(laminatedaluminiumpaperfoil)containingeffervescentgranules

Packsize:

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

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialinstructions.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse

501MiddletonRoad

Chadderton

Oldham

LancashireOL99LY

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/041/001

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Thedateoffirstauthorisation:26 th

August2011

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 16/02/2012 CRN 2108996 page number: 12