ACTONEL PLUS CA & D TABLET 35MG AND 500MG/ 400 IU F

Main information

  • Trade name:
  • ACTONEL PLUS CA & D TABLET 35MG AND 500MG/ 400 IU F
  • Dosage:
  • 35/ 500/ 400 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACTONEL PLUS CA & D TABLET 35MG AND 500MG/400 IU F
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1635/003/002
  • Authorization date:
  • 30-04-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ActonelPlusCa&DTablet35mgand500mg/400IUfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

ActonelPlusCa&DTabletiscomposedofActonel35mgtablets(light-orangetablets)andcalcium/vitaminD3

tablets(whitetablets).

Light-orangetablets

Eachfilm-coatedtabletcontains35mgrisedronatesodium(equivalentto32.5mgrisedronicacid).

Whitetablets

Eachfilm-coatedtabletcontains1250mgcalciumcarbonateequivalentto500mgcalciumand10micrograms(400

IU)colecalciferol(vitaminD).

Excipients:

Eachlight-orangetabletcontainslactose.

Eachwhitetabletcontainssucrose.

Forfulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

Risedronatesodiumtablet:

Oval,light-orange,film-coatedtabletwithRSNononesideand35mgontheother.

Calcium/vitaminDtablet:

Capsule-shaped,white,film-coatedtabletwith“CA+D”ononesideandblankontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpostmenopausalosteoporosis,toreducetheriskofvertebralfractures.

Treatmentofestablishedpostmenopausalosteoporosis,toreducetheriskofhipfractures(seesection5.1).

ActonelPlusCa&DTabletisonlyintendedforuseinassessedpatientsforwhomtheamountofcalciumandvitamin

Dincludedisconsideredtoprovideadequatesupplementation.

4.2Posologyandmethodofadministration

AweeklyunitofActonelPlusCa&DTablet,consistsof1Actonel35mgfilm-coatedtabletand12calcium/vitamin

Dtabletspackagedinablistercard.

Therecommendeddoseinadultsis1Actonel35mgtabletonthefirstdayfollowedonthenextdayby1

calcium/vitaminDtablettwicedailyfor6days.This7-daysequenceisthenrepeatedeachweekstartingwiththe

Actonel35mgtablet.

Actonel35mg(light-orangetablets):

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Theabsorptionofrisedronatesodiumisaffectedbyfood,thustoensureadequateabsorption,patientsshouldtakethe

tablet:

Beforebreakfast:atleast30minutesbeforethefirstfood,othermedicinalproductordrink(otherthanplain

water)oftheday.

Thetabletmustbeswallowedwholeandnotsuckedorchewed.ToaiddeliveryofthetablettothestomachtheActonel

35mgtabletistobetakenwhileinanuprightpositionwithaglassofplainwater(120ml).Patientsshouldnotlie

downfor30minutesaftertakingthetablet(seesection4.4).

Calcium/vitaminD(whitetablets):

Twocalcium/vitaminDtabletsshouldbetakeneachday,oneinthemorningandoneintheevening,for6daysper

weekstartingonthedayaftertheActonel35mgtabletistaken.Theabsorptionofcalciumcanbeaffectedbyfoods

containinghighamountsofoxalicacidandphyticacid(seesection4.5),patientsshouldtakethetabletatleast2hours

aftereatingsuchfoods.

Thetabletmustbeswallowedwholeandnotsuckedorchewed.Thetabletshouldbetakenwithaglassofplainwater

(120ml).

IncasetheActonel35mgtabletdoseismissed,patientsshouldbeinstructedthattheActonel35mgtabletshouldbe

takenonthenextdayinthemorningaccordingtothedosinginstructions.Inthisparticularinstance,patientsshould

thentaketheircalcium/vitaminDtabletonthefollowingday.Patientsshouldbeinstructedthattheyshouldnevertake

theActonel35mgtabletandthecalcium/VitaminD3tabletonthesameday.

Ifthecalcium/vitaminDtabletismissed,thepatientshouldbeinstructedtocontinuetakingthecalcium/vitaminD

tableteachmorningandonetableteachevening,beginningonthedaythemisseddoseisremembered.Patientsshould

beinstructedthattheyshouldnottakethreecalcium/vitaminD

tabletsonthesameday.Anyremainingtabletsinthe

blisterpackattheendoftheweeklycycleshouldbediscarded.

Theoptimaldurationofbisphosphonatetreatmentforosteoporosishasnotbeenestablished.Theneedforcontinued

treatmentshouldbere-evaluatedperiodicallybasedonthebenefitsandpotentialrisksofrisedronateonanindividual

patientbasis,particularlyafter5ormoreyearsofuse.

Elderly:Nodosageadjustmentisnecessarysincebioavailability,distributionandeliminationweresimilarinelderly

(>60yearsofage)comparedtoyoungersubjects.Thishasalsobeenshownintheveryelderly,75yearsoldandabove

inpostmenopausalpopulation.

RenalImpairment:Nodosageadjustmentisrequiredforthosepatientswithmildtomoderaterenalimpairment.The

useofrisedronatesodiumandcalcium/vitaminDiscontraindicatedinpatientswithsevererenalimpairment

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

Paediatricpopulation:Risedronatesodiumisnotrecommendedforuseinchildrenbelowage18duetoinsufficientdata

onsafetyandefficacy(alsoseesection5.1).

4.3Contraindications

Hypersensitivitytorisedronatesodium,calciumcarbonate,colecalciferolortoanyoftheexcipients.

Hypocalcaemia(seesection4.4)

Hypercalcaemia.

Hypercalciuria

Diseasesand/orconditions(suchasprolongedimmobilization)associatedwithhypercalcaemiaand/orhypercalciuria

Nephrolithiasis

Pregnancyandlactation.

Severerenalimpairment(creatinineclearance<30ml/min).

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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

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

Bisphosphonateshavebeenassociatedwithoesophagitis,gastritis,oesophagealulcerationsandgastroduodenal

ulcerations.Thus,cautionshouldbeused:

Inpatientswhohaveahistoryofoesophagealdisorderswhichdelayoesophagealtransitoremptyinge.g.

strictureorachalasia.

Inpatientswhoareunabletostayintheuprightpositionforatleast30minutesaftertakingthetablet.

Ifrisedronateisgiventopatientswithactiveorrecentoesophagealoruppergastrointestinalproblems.

Prescribersshouldemphasisetopatientstheimportanceofpayingattentiontothedosinginstructionsandbealerttoany

signsorsymptomsofpossibleoesophagealreaction.Thepatientsshouldbeinstructedtoseektimelymedicalattention

iftheydevelopsymptomsofoesophagealirritationsuchasdysphagia,painonswallowing,retrosternalpainor

new/worsenedheartburn.

HypocalcaemiashouldbetreatedbeforestartingActonelPlusCa&DTablettherapy.Otherdisturbancesofboneand

mineralmetabolism(i.e.parathyroiddysfunction,hypovitaminosisD)shouldbetreatedatthetimeofstartingActonel

PlusCa&DTablettherapy.

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.

Inpatientswithmildtomoderaterenalimpairmentorahistoryofabsorptiveorrenalhypercalciuria,nephrocalcinosis,

kidneystoneformation,orhypophosphataemia,renalfunction,serumandurinarycalciumandphosphateshouldbe

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Atypicalfracturesofthefemur

Atypicalsubtrochantericanddiaphysealfemoralfractureshavebeenreportedwithbisphosphonatetherapy,primarily

inpatientsreceivinglong-termtreatmentforosteoporosis.Thesetransverseorshortobliquefracturescanoccur

anywherealongthefemurfromjustbelowthelessertrochantertojustabovethesupracondylarflare.Thesefractures

occurafterminimalornotraumaandsomepatientsexperiencethighorgroinpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fracturesareoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureshasalsobeenreported.Discontinuationofbisphosphonate

therapyinpatientssuspectedtohaveanatypicalfemurfractureshouldbeconsideredpendingevaluationofthepatient,

basedonanindividualbenefitriskassessment.

Duringbisphosphonatetreatmentpatientsshouldbeadvisedtoreportanythigh,hiporgroinpainandanypatient

presentingwithsuchsymptomsshouldbeevaluatedforanincompletefemurfracture.

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

Calciumcarbonate/vitaminD:

VitaminDshouldbeusedwithcautioninpatientswithimpairmentofrenalfunctionandtheeffectoncalciumand

phosphatelevelsshouldbemonitored.Theriskofsofttissuecalcificationshouldbetakenintoaccount.Inpatientswith

severerenalinsufficiency,vitaminDintheformofcolecalciferolisnotmetabolisednormallyandanotherformof

vitaminDshouldbeused(seesection4.3)

Duringlong-termtreatment,serumandurinarycalciumlevelsshouldbefollowed.Renalfunctionshouldbemonitored

throughmeasurementofserumcreatinine.Monitoringisespeciallyimportantinelderlypatientsonconcomitanttreatme

withcardiacglycosidesordiuretics(seesection4.5)andinpatientswithahightendencytocalculusformation.Treatme

mustbereducedorsuspendedifurinarycalciumexceeds7.5mmol/24hour(300mg/24hour).Incaseofhypercalcaemi

signsofimpairedrenalfunction,treatmentwithcalcium/vitaminDtabletsshouldbediscontinued.

ThedoseofvitaminDinthetabletsshouldbeconsideredwhenprescribingotherdrugscontainingvitaminD.Addition

dosesofcalciumorvitaminDshouldbetakenunderclosemedicalsupervision.Insuchcasesitisnecessarytomonitor

serumcalciumlevelsandurinarycalciumexcretionfrequently.

Calcium/vitaminDtabletsshouldbeusedwithcautioninpatientssufferingfromsarcoidosisbecauseoftheriskof

increasedmetabolismofvitaminDtoitsactivemetabolite.Inthesepatients,serumcalciumlevelsandurinarycalcium

excretionmustbemonitored.

Calcium/vitaminDtabletsshouldbeusedwithcautioninimmobilisedpatientswithosteoporosisduetotheincreased

riskofhypercalcaemia.Thecalcium/vitaminDtreatmentmightbediscontinuedinprolongedimmobilizationand

shouldonlyberesumedoncethepatientbecomesmobileagain.

Thismedicinalproductcontainssucrose.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

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Ifconsideredappropriaterisedronatesodiummaybeusedconcomitantlywithoestrogensupplementation.

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

willinterferewiththeabsorptionofrisedronatesodium(seesection4.4).

Risedronatesodiumisnotsystemicallymetabolised,doesnotinducecytochromeP450enzymes,andhaslowprotein

binding.

Calciumcarbonate/vitaminD:

Thiazidediureticsreducetheurinaryexcretionofcalcium.Duetoincreasedriskofhypercalcemiaserumcalcium

shouldberegularlymonitoredduringconcomitantuseofthiazidediuretics.

Systemiccorticosteroidsreducecalciumabsorption.Duringconcomitantuse,itmaybenecessarytoincreasethedose

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.

Simultaneoustreatmentwithionexchangeresinssuchascholestyramineorlaxativessuchasparaffinoilmayreduc

gastrointestinalabsorptionofvitaminD.

4.6Fertility,pregnancyandlactation

Thismedicinalproductiscontraindicatedduringpregnancyandlactation(seesection4.3).

Risedronatesodium:

Therearenoadequatedatafromuseofrisedronatesodiuminpregnantwomen.Studiesinanimalshaveshown

reproductivetoxicity(seesection5.3).Thepotentialrisktohumansisunknown.Studiesinanimalsindicatethata

smallamountofrisedronatesodiumpassesintobreastmilk.Risedronatesodiummustnotbeusedduringpregnancyor

bybreast-feedingwomen.

Calciumcarbonate/vitaminD:

Duringpregnancythedailyintakeshouldnotexceed1500mgcalciumand600IUcolecalciferol(15µgvitaminD).

TherearenoindicationsthatvitaminDattherapeuticdosesisteratogenicinhumans.Studiesinanimalshaveshown

reproductivetoxicitywithhighdosesofvitaminD.Inpregnantwomen,overdosesofcalciumandvitaminDshouldbe

avoidedaspermanenthypercalcaemiahasbeenrelatedtoadverseeffectsonthedevelopingfoetus.Calciumand

vitaminDpassintobreastmilk.Calcium1000mg/vitaminD800IUdailydosemustnotbeusedduringpregnancy

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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.

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:

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Skinandsubcutaneoustissuedisorders:

hypersensitivityandskinreactions,includingangioedema,generalisedrash,urticariaandbullousskinreactions,some

severeincludingisolatedreportsofStevens-Johnsonsyndromeandtoxicepidermalnecrolysisandleukocytoclastic

vasculitis.

hairloss.

Immunesystemdisorders:

anaphylacticreaction

Hepatobiliarydisorders:

serioushepaticdisorders.Inmostofthereportedcasesthepatientswerealsotreatedwithotherproductsknownto

causehepaticdisorders.

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyrare):

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,hypercalciuriaandhypercalcaemia.Symptomsofhypercalcaemiamayinclude

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

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

hypercalcaemiamayresultincomaanddeath.Persistentlyhighcalciumlevelsmayleadtoirreversiblerenaldamage

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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:

Bisphosphonatescombinations,ATCCode:M05BB.

VitaminDandanalogues:ATCCode:A11CC05

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.Daily

dosesof2.5mgand5mgwerestudiedandallgroups,includingthecontrolgroups,receivedcalciumandvitaminD(if

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.

Twofurtherplacebocontrolledtrialsenrolledpostmenopausalwomenabove70yearsofagewithorwithout

vertebralfracturesatbaseline.Women70-79yearswereenrolledwithfemoralneckBMDT-score<-3SD

(manufacturer’srange,i.e.-2.5SDusingNHANESIII)andatleastoneadditionalriskfactor.Women>80yearscould

beenrolledonthebasisofatleastonenon-skeletalriskfactorforhipfractureorlowbonemineraldensityatthe

femoralneck.Statisticalsignificanceoftheefficacyofrisedronatesodiumversusplaceboisonlyreachedwhenthetwo

treatmentgroups,2.5mgand5mg,arepooled.Thefollowingresultsareonlybasedona-posteriorianalysisof

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InthesubgroupofpatientswithfemoralneckBMDT-score-2.5SD(NHANESIII)andatleastonevertebral

fractureatbaseline,risedronatesodiumgivenfor3yearsreducedtheriskofhipfracturesby46%relativetothecontrol

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

Datasuggestthatamorelimitedprotectionthanthismaybeobservedintheveryelderly(>80years).Thismay

beduetotheincreasingimportanceofnon-skeletalfactorsforhipfracturewithincreasingage.

Inthesetrials,dataanalysedasasecondaryendpointindicatedadecreaseintheriskofnewvertebralfracturesin

patientswithlowfemoralneckBMDwithoutvertebralfractureandinpatientswithlowfemoralneckBMDwithor

withoutvertebralfracture.

Risedronatesodium5mgdailygivenfor3yearsincreasedBMDrelativetocontrolatthelumbarspine,femoral

neck,trochanterandwristandmaintainedbonedensityatthemid-shaftradius.

Inaone-yearfollow-upofftherapyafterthreeyearstreatmentwithrisedronatesodium5mgdailytherewasrapid

reversibilityofthesuppressingeffectofrisedronatesodiumonboneturnoverrate.

Bonebiopsysamplesfrompostmenopausalwomentreatedwithrisedronatesodium5mgdailyfor2to3years,

showedanexpectedmoderatedecreaseinboneturnover.Boneformedduringrisedronatesodiumtreatmentwasof

normallamellarstructureandbonemineralisation.Thesedatatogetherwiththedecreasedincidenceofosteoporosis

relatedfracturesatvertebralsitesinwomenwithosteoporosisappeartoindicatenodetrimentaleffectonbone

quality.

Endoscopicfindingsfromanumberofpatientswithanumberofmoderatetoseveregastrointestinalcomplaintsin

bothrisedronatesodiumandcontrolpatientsindicatednoevidenceoftreatmentrelatedgastric,duodenalor

oesophagealulcersineithergroup,althoughduodenitiswasuncommonlyobservedintherisedronatesodiumgroup.

Calciumcarbonate/vitaminD:

Incaseofcalciumdeficiency,oralintakeofcalciumsupplementationsupportstheremineralisationoftheskeleton.

VitaminDincreasestheintestinalabsorptionofcalcium.

AdministrationofcalciumandvitaminDcounteractstheincreaseinparathyroidhormone(PTH)whichiscausedby

calciumdeficiencywhichcausesincreasedboneresorption.

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%

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clearanceis122ml/min,withthedifferenceprobablyattributedtoclearanceduetoadsorptiontobone.Therenal

clearanceisnotconcentrationdependent,andthereisalinearrelationshipbetweenrenalclearanceandcreatinine

clearance.Unabsorbedrisedronatesodiumiseliminatedunchangedinfaeces.Afteroraladministrationthe

concentration-timeprofileshowsthreeeliminationphaseswithaterminalhalf-lifeof480hours.

SpecialPopulations

Elderly:nodosageadjustmentisnecessary.

Calciumcarbonate:

Absorption:Calciumcarbonateisconvertedtocalciumchloridebygastricacid.Calciumisabsorbedtotheextentof

about15-25%fromthegastro-intestinaltract

Distributionandmetabolism:99%ofcalciuminthebodyisconcentratedinthehardstructureofbonesandteeth.The

remaining1%ispresentintheintra-andextracellularfluids.About50%ofthetotalbloodcalciumcontentis

physiologicallyactiveionisedformwithapproximately10%beingcomplexedtocitrate,phosphateorotheranions,the

remaining40%beingboundtoproteins,principallyalbumin.

Elimination:Calciumiseliminatedthroughfaeces,urineandsweat.Renalexcretiondependsonglomerularfiltration

andcalciumtubularreabsorption.

VitaminD:

Absorption:VitaminDiswellabsorbedinthesmallintestine.

Distributionandmetabolism:Cholecalciferolanditsmetabolitescirculateinthebloodboundtoaspecificglobulin.

Cholecalciferolisconvertedintheliverbyhydroxylationtotheactiveform25-hydroxycolecalciferol.Itisthenfurther

convertedinthekidneysto1,25hydroxycolecalciferol.1,25hydroxycolecalciferolisthemetaboliteresponsiblefor

increasingcalciumabsorption.VitaminDwhichisnotmetabolisedisstoredinadiposeandmuscletissues.

Elimination:VitaminDisexcretedinfaecesandurine.

5.3Preclinicalsafetydata

Risedronatesodium:

Intoxicologicalstudiesinratanddogdosedependentlivertoxiceffectsofrisedronatesodiumwereseen,primarilyas

enzymeincreaseswithhistologicalchangesinrat.Theclinicalrelevanceoftheseobservationsisunknown.Testicular

toxicityoccurredinratanddogatexposuresconsideredinexcessofthehumantherapeuticexposure.Doserelated

incidencesofupperairwayirritationwerefrequentlynotedinrodents.Similareffectshavebeenseenwithother

bisphosphonates.Lowerrespiratorytracteffectswerealsoseeninlongertermstudiesinrodents,althoughtheclinical

significanceofthesefindingsisunclear.Inreproductiontoxicitystudiesatexposuresclosetoclinicalexposure

ossificationchangeswereseeninsternumand/orskulloffoetusesfromtreatedratsandhypocalcemiaandmortalityin

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

rabbit,althoughdataareonlyavailableonasmallnumberofrabbits.Maternaltoxicitypreventedtestingofhigher

doses.Studiesongenotoxicityandcarcinogenesisdidnotshowanyparticularriskforhumans.

Calciumcarbonate/vitaminD:

Atdosesfarhigherthanthehumantherapeuticrange,teratogenicityhasbeenobservedinanimalstudies(seesection

4.6).Thereisnofurtherinformationofrelevancetothesafetyassessmentinadditiontowhatisstatedinotherpartsof

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6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Light-orangetablet:

Tabletcore: Lactosemonohydrate

Cellulosemicrocrystalline

CrospovidoneA

Magnesiumstearate.

Filmcoating:Hypromellose

Macrogol

Hyprolose

Silicondioxide

Titaniumdioxide(E171)

Ironoxideyellow(E172)

Ironoxidered(E172).

Whitetablets:

Tabletcore: Maltodextrin

Cellulosepowder

Liquidparaffin

Silicondioxide

Butylhydroxytoluene(E321)

Triglyceridesmedium-chain

Maizestarchmodified

Sodiumaluminiumsilicate

Gelatin

Sucrose.

Filmcoating:Titaniumdioxide(E171)

Hypromellose

Polysorbate80

Triacetin

Carnaubawax.

6.2Incompatibilities

Notapplicable.

6.3Shelflife

2years.

6.4Specialprecautionsforstorage

Storebelow30°C.

6.5Natureandcontentsofcontainer

Eachweeklyunitcontains:

Aluminium/Aluminiumfoilblistercontainingonerisedronatesodium(light-orange)film-coatedtabletandtwelve

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Packsizes:

1weeklyunit:1x(1risedronatesodiumfilm-coatedtabletand12Calcium/vitaminDfilm-coatedtablets)

2weeklyunits:2x(1risedronatesodiumfilm-coatedtabletand12Calcium/vitaminDfilm-coatedtablets)

4weeklyunits:4x(1risedronatesodiumfilm-coatedtabletand12Calcium/vitaminDfilm-coatedtablets)

12weeklyunits:12x(1risedronatesodiumfilm-coatedtabletand12Calcium/vitaminDfilm-coatedtablets)

16weeklyunits:16x(1risedronatesodiumfilm-coatedtabletand12Calcium/vitaminDfilm-coatedtablets)

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

WarnerChilcottUKLimited

OldBelfastRoad

Millbrook

Larne

CountyAntrim

BT402SH

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1635/3/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:4thJuly2008.

10DATEOFREVISIONOFTHETEXT

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