CLASTEON 800MG FILM-COATED TABLETS

Main information

  • Trade name:
  • CLASTEON 800MG FILM-COATED TABLETS
  • Dosage:
  • 800 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • CLASTEON 800MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1312/012/001
  • Authorization date:
  • 11-11-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Clasteon800mgFilm-coatedTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains1000mgofdisodiumclodronatetetrahydrate,equivalentto800mgofanhydroussodium

clodronate.Eachtabletcontains128.24mgsodium.

Forafulllistofexcipients,see6.1.

3PHARMACEUTICALFORM

Filmcoatedtablets.

White,oval,convextabletwithbreakline.Thescorelineisonlytofacilitatebreakingforeaseofswallowingandnot

todivideintoequaldoses.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Sodiumclodronateisindicatedforthemanagementofosteolyticlesions,hypercalcaemiaandbonepainassociated

withskeletalmetastasesinpatientswithcarcinomaofthebreastormultiplemyeloma.Sodiumclodronatetabletsare

alsoindicatedforthemaintenanceofclinicallyacceptableserumcalciumlevelsinpatientswithhypercalcaemiaof

malignancyinitiallytreatedwithanintravenousbisphosphonate.

4.2Posologyandmethodofadministration

Adequatefluidintakeshouldbemaintainedduringtreatment.AClasteon800mgtabletmaybedividedintotwoto

easeswallowing,butthehalveshavetobetakenatthesametimeofadministration.Clasteontabletsshouldnotbe

crushedordissolvedbeforeintake.

Adults:Therecommendeddailydoseis2tablets(1600mgsodiumclodronate)takenasasingledose.Ifclinically

necessary,thedosemaybeincreased,butisnotrecommendedtoexceed3200mgdaily.

Intravenousclodronateisrecommendedforthetreatmentofhypercalcaemiaduetomalignancy.However,iforal

therapyisused,ahighstartingdoseof2400or3200mgdailyshouldbeusedand,dependingontheindividual

response,thiscanbereducedgraduallyto1600mgdailyinordertomaintainnormocalcaemia.

Whenhigherdailydosesareused,thepartofthedoseexceeding1600mgshouldbetakenseparately(asasecond

dose)asrecommendedbelow.

Thesingledailydoseandthefirstdoseoftwoshouldpreferablybetakeninthemorningonanemptystomach

togetherwithaglassofwater.Thepatientshouldthenrefrainfromeating,drinking(otherthanplainwater),and

takinganyotheroraldrugsforonehour.

Whentwicedailydosingisused,thefirstdoseshouldbetakenasrecommendedabove.Theseconddoseshouldbe

takenbetweenmeals,morethantwohoursafterandonehourbeforeeating,drinking(otherthanplainwater),or

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Clodronateshouldinnocasebetakenwithmilk,foodordrugscontainingcalciumorotherdivalentcationsbecause

theyimpairtheabsorptionofclodronate.

Elderly:Therearenospecialdosagerecommendationsintheelderly.Clinicaltrialshaveincludedpatientsover65

yearsandnoadversereactionsspecifictothisagegrouphavebeenreported.

Children:Safetyandefficacyinchildrenhavenotbeenestablished.

Useinrenalimpairment:Clodronateiseliminatedmainlyviathekidneys.Therefore,itshouldbeusedwithcaution

inpatientswithrenalfailure;dailydosesexceeding1600mgshouldnotbeusedcontinuously.

Inpatientswithmildrenalfailurewithcreatinineclearance50–80ml/min.nodosagereductionisrecommended.In

patientswithmoderaterenalfailure(creatinineclearance30-49ml/min)thedailydoseshouldbereducedto1200mg

sodiumclodronate.

Inpatientswithsevererenalfailurewithcreatinineclearance10–29ml/min.thedailydoseshouldbereducedtohalf

theadultdose,i.e.800mgsodiumclodronate.Sodiumclodronateiscontraindicatedinpatientswithcreatinine

clearancebelow10ml/min.

DosageforPatientswithRenalFailure

Theoralbioavailabilityofbisphosphonatesispoor.Bioequivalencestudieshaveshownappreciabledifferencesin

bioavailabilitybetweendifferentoralformulationsofsodiumclodronate,aswellasmarkedinterandintrapatient

variability.Doseadjustmentmayberequirediftheformulationischanged.

4.3Contraindications

Sodiumclodronatetabletsarecontraindicatedinpatientswithsevererenalfailurewherecreatinineclearanceless

than10ml/min,hypersensitivitytotheactivesubstanceortoanyoftheexcipientsandinpatientsreceiving

concomitanttreatmentwithotherbisphosphonates.

4.4Specialwarningsandprecautionsforuse

Adequatefluidintakeshouldbemaintainedduringtreatment.

Sodiumclodronateshouldbeadministeredwithcaretopatientswithrenalinsufficiency.Itisrecommendedthat

appropriatemonitoringofhydrationstatusandrenalfunctionwithserumcreatininemeasurementbecarriedoutduring

treatment.Serumcalciumshouldbemonitoredperiodically.

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimensincludingprimarilyintravenouslyadministered

bisphosphonates.Manyofthesepatientswerealsoreceivingchemotherapyandcorticosteroids.Osteonecrosisofthe

jawhasalsobeenreportedinpatientswithosteoporosisreceivingoralbisphosphonates.

Adentalexaminationwithappropriatepreventivedentistryshouldbeconsideredpriortotreatmentwith

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

poororalhygiene).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

Degreeofrenal

failure CreatinineClearance

(ml/min) Dose

Mild 50-80 1600mgdaily(nodose

reduction

recommended)

Moderate 30-49 1200mgdaily

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Forpatientsrequiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationof

bisphosphonatetreatmentreducestheriskofosteonecrosisofthejaw.

Thismedicinalproductcontains128.24mgsodiumpertablet.Tobetakenintoconsiderationbypatientsona

controlledsodiumdiet.

Clinicaljudgmentofthetreatingphysicianshouldguidethemanagementplanofeachpatientbasedonindividual

benefit/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.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantuseofotherbisphosphonatesiscontraindicated.

Asaminoglycosidescancausehypocalcaemia,concomitantclodronateshouldbeadministeredwithcaution.

PatientsreceivingNSAID'sinadditiontosodiumclodronatehavedevelopedrenaldysfunction.However,a

synergisticactionhasnotbeenestablished.

Concomitantuseofestramustinephosphatewithclodronatehasbeenreportedtoincreasetheserumconcentrationof

estramustinephosphateby80%atthemaximum.

Sodiumclodronateformscomplexeswithdivalentions,andthereforesimultaneousadministrationwithfood,antacids,

andmineralsupplementsmayimpairabsorption.

4.6Fertility,pregnancyandlactation

Therearelimitedamountofdatafromtheuseofclodronateinpregnantwomen.Sodiumclodronateisnot

recommendedduringpregnancyandinwomenofchildbearingpotentialnotusingeffectivecontraception.Although

inanimalsclodronatepassesthroughtheplacentalbarrier,itisnotknownifitpassesintothefoetusinhumans.

Furthermore,itisnotknownifclodronatecancausefoetaldamageoraffectreproductioninhumans.Studiesin

animalshaveshownreproductivetoxicity(seesection5.3).

Itisunknownwhetherclodronateisexcretedinhumanmilk.Arisktothesucklingchildcannotbeexcluded.Breast-

feedingshouldbediscontinuedduringtreatmentwithsodiumclodronate.

4.7Effectsonabilitytodriveandusemachines

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4.8Undesirableeffects

Themostcommonreporteddrugreactionisdiarrhoeawhichisusuallymildandoccursmorecommonlywithhigher

doses.

Theseadversereactionsmayoccurwhenusingsodiumclodronate:

SystemOrgan

Class Common

1/100to<1/10 Rare

1/10,000to<

1/1,000 Frequency

unknown

Metabolismand

nutritiondisorders Asymptomatic

hypocalcaemia. Symptomatic

hypocalcaemia.

Increasedlevelsof

serumparathyroid

hormoneassociated

withdecreasedserum

calciumlevels.

Increasedlevelsof

serumalkaline

phosphatase.*

Gastrointestinal

disorders Diarrhoea**

Nausea**

Vomiting**

Hepatobiliary

disorders Levelsof

transaminases

increased–usually

withinnormalrange. Levelsof

transaminases

increasedtomore

thantwicethenormal

rangewithout

associatedabnormal

hepaticfunction.

Skinand

subcutaneoustissue

disorders Hypersensitivity

reactionmanifesting

asskinreactione.g.

pruritus,urticaria,

exfoliativedermatitis

Respiratory,

thoracicand

mediastinal

disorders Bronchospasmin

patientswithand

withoutaprevious

historyofasthma. Impairmentof

respiratory

functionin

patientswith

aspirin-sensitive

asthma.

Hypersensitivity

reactions

manifestingas

respiratory

disorder.

Renalandurinary

disorders Impairmentof

renalfunction

(elevationof

serumcreatinine

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*inpatientswithmetastaticdisease,mayalsobeduetohepaticandbonedisease.

**usuallymild–useofthedivideddoseregimenratherthanasingledailydosemayimprovegastro-intestinaltolerance.

ThemostappropriateMedDRAtermisusedtodescribeacertainreactionanditssynonymsandrelatedconditions.

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyrare):

severerenal

damage.

Singlecasesof

renalfailure,in

rarecaseswith

fataloutcome,

especiallywith

concomitantuse

ofNSAIDs,most

oftendiclofenac.

Musculoskeletal

andconnective

tissuedisorders Isolatedcasesof

osteonecrosisof

thejaw,primarily

inpatients

previouslytreated

withamino-

bisphosphonates

suchas

zoledronateand

pamidronate(see

section4.4).

Severebone,joint

and/ormuscle

painhasbeen

reportedin

patientstaking

sodium

clodronate.

However,such

reportshavebeen

infrequentandin

randomised

placebocontrolled

studiesno

differencesare

apparentbetween

placeboand

sodiumclodronate

treatedpatients.

Theonsetof

symptomsvaried

fromdaysto

severalmonths

afterstarting

sodium

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4.9Overdose

Symptoms:

Increasesinserumcreatinineandrenaldysfunctionhavebeenreportedwithhighintravenousdosesofclodronate.It

istheoreticallypossiblethathypocalcaemiamaydevelopupto2or3daysfollowingtheoverdose.

Treatment:

Treatmentofoverdoseshouldbesymptomatic.Adequatehydrationshouldbeensured,andrenalfunctionandserum

calciumshouldbemonitored.Serumcalciumshouldbemonitoredandoralorparenteralcalciumsupplementation

maybeneeded.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Bisphosphonates

ATCcode:M05BA02

Clodronateisabisphosphonate,(formerlydiphosphonates),agroupofanaloguesofpyrophosphate,whichhavebeen

shown,invitro,toinhibittheformationanddissolutionofcalciumphosphate(hydroxyapatite).Invivo,theyhave

beenshowntoinhibitboneresorptiontoagreaterorlesserextent,dependingonthecompound,andclodronateis

oneofthemosteffectiveinthisrespect.

However,themostimportantmechanismofactionofclodronateisitsinhibitoryeffectonosteoclasticbone

resorption.Clodronateinhibitsboneresorptioninducedinseveralways.Ingrowingrats,thisinhibitionofbone

resorptionathighdosesofclodronatecausesbroadeningoflongbonemetaphyses.

Inovariectomizedrats,boneresorptionisinhibitedatdosesaslowas3mg/kgadministeredsubcutaneouslyoncea

week.Atpharmacologicaldosesclodronatepreventsreductionofbonestrength.

Thepharmacologicalefficacyofclodronatehasbeendemonstratedindifferenttypesofpreclinicalexperimental

modelsofosteoporosis,includingestrogendeficiency.Clodronatehasbeenshowntoinhibitdose-dependentlybone

resorption,withoutdeleteriouseffectsonmineralizationoronotherbonequalityaspects.Boneresorptionin

experimentalrenalosteodystrophyisalsoinhibitedbyclodronate.

Theabilityofclodronatetoinhibitboneresorptioninhumanshasbeenestablishedinhistological,kineticand

biochemicalstudies.However,theexactmechanismsofboneresorptioninhibitionarepartlyunknown.Clodronate

suppressestheactivityofosteoclasts,reducingtheserumcalciumconcentrationandurinaryexcretionofcalciumand

hydroxyproline.Clodronatepreventsbonelossassociatedwithbreastcancerinthehipandlumbarspineinpre-and

postmenopausalwomen.Whenclodronateisusedaloneatdosesinhibitingboneresorption,noeffectsonnormal

bonemineralizationinhumanshavebeenobserved.Adecreaseinfractureriskhasbeenobservedinpatientswith

breastcancerandmultiplemyeloma.

5.2Pharmacokineticproperties

Absorption

Aswithotherbisphosphonates,thegastrointestinalabsorptionofclodronateislow,about2%.Theabsorptionof

clodronateisrapid,thepeakserumconcentrationafterasingleoraldoseisreachedwithin30minutes.Duetothe

strongaffinityofclodronateforcalciumandotherdivalentcations,theabsorptionisnegligiblewhenclodronateis

takenwithmealsordrugscontainingdivalentcations.Inastudy,whereclodronateadministration2hbefore

breakfastwasusedasthereferencetreatment,adose-breakfastintervalof1hor0.5hdecreasedthebioavailability

ofclodronate,butthedifferencewasnotstatisticallysignificant(relativebioavailability91%and69%,respectively).

Inaddition,thereislargeinter-andintraindividualvariationinthegastrointestinalabsorptionofclodronate.Despite

thelargeintraindividualvariationintheabsorptionofclodronate,theexposuretoclodronateremainsconstantduring

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Distributionandelimination

Theplasmaproteinbindingofclodronateislow,andthedistributionvolumeis20-50l.Theeliminationofclodronate

fromserumischaracterizedbytwoclearlydistinguishedphases:thedistributionphasewithahalf-lifeofabout2

hours,andaneliminationphasewhichisveryslowbecauseclodronateisstronglyboundtobone.Clodronateis

mainlyeliminatedviathekidneys.About80%oftheabsorbedclodronateappearsinurineduringafollow-upofa

fewdayshesubstancewhichisboundtobone(about20%oftheabsorbedamount)isexcretedmoreslowly,andthe

renalclearanceisabout75%oftheplasmaclearance.

Clodronateisremovedbyhaemodialysis.When300mgwasgivenbyslowinfusion2hbeforehaemodialysis,35%

oftheclodronatedosewascollectedinthe4hourdialysate.

Characteristicsinpatients

Becauseclodronateaffectsbonethereisnoclearrelationshipbetweenplasmaorbloodconcentrationsofclodronate

andthetherapeuticactivityorwithadversedrugreactions.Apartfromrenalinsufficiency,whichdecreasestherenal

clearanceofclodronate,thepharmacokineticprofileisnotaffectedbyanyknownfactorrelatedtoage,drug

metabolismorotherpathologicalconditions.

5.3Preclinicalsafetydata

Systemictolerance:

Repeateddoseoralandintravenoustoxicitystudiesinratsandmini-pigsupto6to12monthsdurationrespectively

havebeenperformed.Atoraldailydosesupto480mg/kginratsand800mg/kginmini-pigsnotestsubstance

relatedmortalitywasnoted.Inthesestudies,theeffectofclodronatewasobservedinthefollowingorgans(the

observedchangeswithinbrackets):bone(sclerosisrelatedtothepharmacologicaleffectsofclodronate),

gastrointestinaltract(irritation),blood(lymphopenia,effectsonhemostasis),kidneys(dilatedtubules,proteinuria),

andliver(elevationofserumtransaminases).

Reproductiontoxicity:

Inreproductivetoxicitystudiesintherat,clodronateatexposuresatorbelowclinicalexposurelevelscaused

maternalmortalityaroundthetimeofparturitionandisbelievedtobeasaresultofhypocalcaemia.

Interatologystudiesinratsandrabbitsatoraldailydosagesof200mg/kgand300mg/kgrespectively(0.5to2times

themaximumclinicaldosebasedonbodysurfacearea,mg/m 2

),noadverseorteratogeniceffectswereobservedin

theoffspring.Athigherdosesassociatedwithmaternaltoxicity,therewasreducedlittersizeintherabbitanda

reductioninfoetalbodyweight,reducedossificationandrenalpelvisdilationintherat.

Infertilitystudiesintherat,clodronate600mg/kg/dayinmaleswasassociatedwithreducedbodyweight,lesionsin

thetestesandepididymidesandreducedmatingperformance.

Afteronemonthofsubcutaneousadministrationofclodronatetonewbornrats,skeletalchangesresembling

osteopetrosiswerefound,whicharerelatedtothepharmacologicaleffectsofclodronate.

Carcinogenicity:

Clodronatehasnotshowngenotoxicpotential.Nocarcinogeniceffectshavebeenobservedinlongtermstudieswith

ratsandmice.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Starchpregelatinized,microcrystallinecellulose,colloidalsilicondioxide,sodiumstarchglycolate(typeA)and

magnesiumstearate.Thetabletcoatingcontains:hypromellose,titaniumdioxide(E171)andmacrogol400

6.2Incompatibilities

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6.3Shelflife

PVC/PVDC/aluminiumblisterpacks:4years.

6.4Specialprecautionsforstorage

Nospecialprecautionsforstorage.

6.5Natureandcontentsofcontainer

PVC/PVDC/aluminiumblisterpackscontaining10,30or60tablets.Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialinstructions.

7MARKETINGAUTHORISATIONHOLDER

BeaconPharmaceuticalsLimited

85HighStreet

TunbridgeWells

KentTN11YG

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1312/12/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:11November2011

10DATEOFREVISIONOFTHETEXT

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