ACTONEL ONCE A WEEK

Main information

  • Trade name:
  • ACTONEL ONCE A WEEK
  • Dosage:
  • 35 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACTONEL ONCE A WEEK
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1447/004/001
  • Authorization date:
  • 05-09-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

ActonelOnceaWeek35mgFilm-coatedTablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains35mgrisedronatesodium(equivalentto32.5mgrisedronicacid).

Excipient:Eachfilm-coatedtabletcontainslactose.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromtheUKandItaly:

Ovallight-orangefilm-coatedtabletwith‘RSN’ononesideand‘35mg’ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpostmenopausalosteoporosis,toreducetheriskofvertebralfractures.Treatmentofestablished

postmenopausalosteoporosis,toreducetheriskofhipfractures(seesection5.1).

Treatmentofosteoporosisinmenathighriskoffractures.(seesection5.1).

4.2Posologyandmethodofadministration

Therecommendeddoseinadultsisone35mgtabletorallyonceaweek.Thetabletshouldbetakenonthesameday

eachweek.

Theabsorptionofrisedronatesodiumisaffectedbyfood,thustoensureadequateabsorptionpatientsshouldtake

ActonelOnceaWeek35mg:

Beforebreakfast:Atleast30minutesbeforethefirstfood,othermedicinalproductordrink(otherthanplain

water)oftheday.

Patientsshouldbeinstructedthatifadoseismissed,oneActonelOnceaWeek35mgtabletshouldbetakenontheday

thatthetabletisremembered.Patientsshouldthenreturntotakingonetabletonceaweekonthedaythetabletis

normallytaken.Twotabletsshouldnotbetakenonthesameday.

Thetabletmustbeswallowedwholeandnotsuckedorchewed.ToaiddeliveryofthetablettothestomachActonel

OnceaWeek35mgistobetakenwhileinanuprightpositionwithaglassofplainwater(>120ml).Patientsshould

notliedownfor30minutesaftertakingthetablet(seesection4.4).

SupplementalcalciumandvitaminDshouldbeconsideredifthedietaryintakeisinadequate.

Theoptimaldurationofbisphosphonatetreatmentforosteoporosishasnotbeenestablished.Theneedforcontinued

treatmentshouldbere-evaluatedperiodicallybasedonthebenefitsandpotentialrisksofrisedronateonanindividual

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Elderly:Nodosageadjustmentisnecessarysincebioavailability,distributionandeliminationweresimilarinelderly

(>60yearsofage)comparedtoyoungersubjects.

Thishasalsobeenshownintheveryelderly,75yearsoldandabovepostmenopausalpopulation.

RenalImpairment:Nodosageadjustmentisrequiredforthosepatientswithmildtomoderaterenalimpairment.The

useofrisedronatesodiumiscontraindicatedinpatientswithsevererenalimpairment(creatinineclearancelowerthan

30ml/min)(seesections4.3and5.2).

Paediatricpopulation:Risedronatesodiumisnotrecommendedforuseinchildrenbelowage18duetoinsufficientdata

onsafetyandefficacy(alsoseesection5.1).

4.3Contraindications

Knownhypersensitivitytorisedronatesodiumortoanyoftheexcipients.

Hypocalcaemia(seesection4.4).

Pregnancyandlactation.

Severerenalimpairment(creatinineclearance<30ml/min).

4.4Specialwarningsandprecautionsforuse

Foods,drinks(otherthanplainwater)andmedicinalproductscontainingpolyvalentcations(suchascalcium,

magnesium,ironandaluminium)interferewiththeabsorptionofbisphosphonatesandshouldnotbetakenatthesame

timeasActonelOnceaWeek35mg(seesection4.5).Inordertoachievetheintendedefficacy,strictadherenceto

dosingrecommendationsisnecessary(seesection4.2).

Efficacyofbisphosphonatesinthetreatmentofosteoporosisisrelatedtothepresenceoflowbonemineraldensity

and/orprevalentfracture.

Highageorclinicalriskfactorsforfracturealonearenotsufficientreasonstoinitiatetreatmentofosteoporosiswitha

bisphosphonate.

Theevidencetosupportefficacyofbisphosphonatesincludingrisedronateintheveryelderly(>80years)islimited

(seesection5.1).

Bisphosphonateshavebeenassociatedwithoesophagitis,gastritis,oesophagealulcerationsandgastroduodenal

ulcerations.Thus,cautionshouldbeused:

Inpatientswhohaveahistoryofoesophagealdisorderswhichdelayoesophagealtransitoremptyinge.g.

strictureorachalasia

Inpatientswhoareunabletostayintheuprightpositionforatleast30minutesaftertakingthetablet.

Ifrisedronateisgiventopatientswithactiveorrecentoesophagealoruppergastrointestinalproblems.

Prescribersshouldemphasisetopatientstheimportanceofpayingattentiontothedosinginstructionsandbealertto

anysignsandsymptomsofpossibleoesophagealreaction.Thepatientsshouldbeinstructedtoseektimelymedical

attentioniftheydevelopsymptomsofoesophagealirritationsuchasdysphagia,painonswallowing,retrosternalpain

ornew/worsenedheartburn.

HypocalcaemiashouldbetreatedbeforestartingActonelOnceaWeek35mgtherapy.Otherdisturbancesofboneand

mineralmetabolism(i.e.parathyroiddysfunction,hypovitaminosisD)shouldbetreatedatthetimeofstartingActonel

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Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimensincludingprimarilyintravenouslyadministered

bisphophonates.Manyofthesepatientswerealsoreceivingchemotherapyandcorticosteroids.Osteonecrosisofthejaw

hasalsobeenreportedinpatientswithosteoporosisreceivingoralbisphosphonates.

Adentalexaminationwithappropriatepreventivedentistryshouldbeconsideredpriortotreatmentwith

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

poororalhygiene).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbisphosphonatetherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbisphosphonatetreatment

reducestheriskofosteonecrosisofthejaw.

Clinicaljudgmentofthetreatingphysicianshouldguidethemanagementplanofeachpatientbasedonindividual

benefit/riskassessment.

Thismedicinecontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

deficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Atypicalfractureofthefemur

Atypicalsubtrochantericanddiaphysealfemoralfractureshavebeenreportedwithbisphosphonatetherapy,primarily

inpatientsreceivinglong-termtreatmentforosteoporosis.Thesetransverseorshortoblique,fracturescanoccur

anywherealongthefemurfromjustbelowthelessertrochantertojustabovethesupracondylarflare.Thesefractures

occurafterminimalornotraumaandsomepatientsexperiencethighorgroinpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fracturesareoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureshasalsobeenreported.Discontinuationofbisphosphonate

therapyinpatientssuspectedtohaveanatypicalfemurfractureshouldbeconsideredpendngevaluationofthepatient,

basedonanindividualbenefitriskassessment.

Duringbisphosphonatetreatmentpatientsshouldbeadvisedtoreportanythigh,hiporgroinpainandanypatient

presentingwithsuchsymptomsshouldbeevaluatedforanincompletefemurfracture.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Noformalinteractionstudieshavebeenperformed,howevernoclinicallyrelevantinteractionswithothermedicinal

productswerefoundduringclinicaltrials.IntherisedronatesodiumPhaseIIIosteoporosisstudieswithdailydosing,

acetylsalicylicacidorNSAIDusewasreportedby33%and45%ofpatientsrespectively.InthePhaseIIIonceaweek

studyinpostmenopausalwomen,acetylsalicylicacidorNSAIDusewasreportedby57%and40%ofpatients

respectively.AmongregularacetylsalicylicacidorNSAIDusers(3ormoredaysperweek)theincidenceofupper

gastrointestinaladverseeventsinrisedronatesodiumtreatedpatientswassimilartothatincontrolpatients.

Ifconsideredappropriaterisedronatesodiummaybeusedconcomitantlywithoestrogensupplementation(forwomen

only).

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

willinterferewiththeabsorptionofActonelOnce-a-Week35mg(seesection4.4).

Risedronatesodiumisnotsystemicallymetabolised,doesnotinducecytochromeP450enzymes,andhaslowprotein

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4.6Fertility,pregnancyandlactation

Therearenoadequatedatafromtheuseofrisedronatesodiuminpregnantwomen.Studiesinanimalshaveshown

reproductivetoxicity(see5.3).Thepotentialriskforhumansisunknown.Studiesinanimalsindicatethatasmall

amountofrisedronatesodiumpassintobreastmilk.

ActonelOnce-a-Week35mgmustnotbeusedduringpregnancyorbybreast-feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

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;frequencybasedonadverse

event/laboratory/rechallengefindingsinearlierclinicaltrials.

Inaone-year,double-blind,multicentrestudycomparingrisedronatesodium5mgdaily(n=480)andrisedronate

sodium35mgweekly(n=485)inpostmenopausalwomenwithosteoporosis,theoverallsafetyandtolerabilityprofiles

weresimilar.Thefollowingadditionaladverseexperiencesconsideredpossiblyorprobablydrugrelatedby

investigatorshavebeenreported(incidencegreaterinrisedronate35mgthaninrisedronatesodium5mggroup):

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

Ina2-yearstudyinmenwithosteoporosis,theoverallsafetyandtolerabilityweresimilarbetweenthetreatmentand

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Laboratoryfindings:Early,transient,asymptomaticandmilddecreasesinserumcalciumandphosphatelevelshave

beenobservedinsomepatients.

Thefollowingadditionaladversereactionshavebeenreportedduringpost-marketinguse(frequencyunknown):

Eyedisorders:

iritis,uveitis

Muskuloskeletalandconnectivetissuesdisorders:

osteonecrosisofthejaw

Skinandsubcutaneoustissuedisorders:

hypersensitivityandskinreactions,includingangioedema,generalisedrash,urticariaandbullousskinreactions,some

severeincludingisolatedreportsofStevensJohnsonsyndromeandtoxicepidermalnecrolysisandleukocytoclastic

vasculitis.

hairloss

Immunesystemdisorders:

anaphylacticreaction

Hepatobiliarydisorders:

serioushepaticdisorders.Inmostofthereportedcasesthepatientswerealsotreatedwithotherproductsknownto

causehepaticdisorders.

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyrare):Atypical

subtrochantericanddiaphysealfemoralfractures(bisphosphonateclassadversereaction)

4.9Overdose

Nospecificinformationisavailableonthetreatmentofoverdosewithrisedronatesodium.

Decreasesinserumcalciumfollowingsubstantialoverdosemaybeexpected.Signsandsymptomsofhypocalcaemia

mayalsooccurinsomeofthesepatients.

Milkorantacidscontainingmagnesium,calciumoraluminiumshouldbegiventobindrisedronateandreduce

absorptionofrisedronatesodium.Incasesofsubstantialoverdose,gastriclavagemaybeconsideredtoremove

unabsorbedrisedronatesodium.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:Bisphosphonates

ATCCode:M05BA07.

Risedronatesodiumisapyridinylbisphosphonatethatbindstobonehydroxyapatiteandinhibitsosteoclast-mediated

boneresorption.Theboneturnoverisreducedwhiletheosteoblastactivityandbonemineralisationispreserved.In

preclinicalstudiesrisedronatesodiumdemonstratedpotentanti-osteoclastandantiresorptiveactivity,anddose

dependentlyincreasedbonemassandbiomechanicalskeletalstrength.Theactivityofrisedronatesodiumwas

confirmedbymeasuringbiochemicalmarkersforboneturnoverduringpharmacodynamicandclinicalstudies.In

studiesofpost-menopausalwomen,decreasesinbiochemicalmarkersofboneturnoverwereobservedwithin1month

andreachedamaximumin3-6months.DecreasesinbiochemicalmarkersofboneturnoverweresimilarwithActonel

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Inastudyinmenwithosteoporosis,decreasesinbiochemicalmarkersofboneturnoverwereobservedattheearliest

timepointof3monthsandcontinuedtobeobservedat24months.

TreatmentofPostmenopausalOsteoporosis:

Anumberofriskfactorsareassociatedwithpostmenopausalosteoporosisincludinglowbonemass,lowbonemineral

density,earlymenopause,ahistoryofsmokingandafamilyhistoryofosteoporosis.Theclinicalconsequenceof

osteoporosisisfractures.Theriskoffracturesisincreasedwiththenumberofriskfactors.

BasedoneffectsonmeanchangeinlumbarspineBMD,ActonelOnceaWeek35mg(n=485)wasshowntobe

equivalenttoActonel5mgdaily(n=480)inaone-year,double-blind,multicentrestudyofpostmenopausalwomen

withosteoporosis

Theclinicalprogrammeforrisedronatesodiumadministeredoncedailystudiedtheeffectofrisedronatesodiumonthe

riskofhipandvertebralfracturesandcontainedearlyandlatepostmenopausalwomenwithandwithoutfracture.Daily

dosesof2.5mgand5mgwerestudiedandallgroups,includingthecontrolgroups,receivedcalciumandvitaminD(if

baselinelevelswerelow).Theabsoluteandrelativeriskofnewvertebralandhipfractureswereestimatedbyuseofa

time-to-firsteventanalysis.

Twoplacebo-controlledtrials(n=3661)enrolledpostmenopausalwomenunder85yearswithvertebralfractures

atbaseline.Risedronatesodium5mgdailygivenfor3yearsreducedtheriskofnewvertebralfracturesrelative

tothecontrolgroup.Inwomenwithrespectivelyatleast2oratleast1vertebralfractures,therelativerisk

reductionwas49%and41%respectively(incidenceofnewvertebralfractureswithrisedronatesodium18.1%

and11.3%,withplacebo29.0%and16.3%,respectively).Theeffectoftreatmentwasseenasearlyastheendof

thefirstyearoftreatment.Benefitswerealsodemonstratedinwomenwithmultiplefracturesatbaseline.

Risedronatesodium5mgdailyalsoreducedtheyearlyheightlosscomparedtothecontrolgroup.

Twofurtherplacebocontrolledtrialsenrolledpostmenopausalwomenabove70yearswithorwithoutvertebral

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

range,i.e.-2.5SDusingNHANESIII)andatleastoneadditionalriskfactor.Women>80yearscouldbe

enrolledonthebasisofatleastonenon-skeletalriskfactorforhipfractureorlowbonemineraldensityatthe

femoralneck.Statisticalsignificanceoftheefficacyofrisedronateversusplaceboisonlyreachedwhenthetwo

treatmentgroups2.5mgand5mgarepooled.Thefollowingresultsareonlybasedon-posteriorianalysisof

subgroupsdefinedbyclinicalpractiseandcurrentdefinitionsofosteoporosis:

-InthesubgroupofpatientswithfemoralneckBMDT-score<-2.5SD(NHANESIII)andatleastonevertebral

fractureatbaseline,risedronatesodiumgivenfor3yearsreducedtheriskofhipfracturesby46%relativetothecontrol

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

-Datasuggestthatamorelimitedprotectionthanthismaybeobservedintheveryelderly(>80years).Thismaybe

duetotheincreasingimportanceofnon-skeletalfactorsforhipfracturewithincreasingage.

Inthesetrials,dataanalysedasasecondaryendpointindicatedadecreaseintheriskofnewvertebralfracturesin

patientswithlowfemoralneckBMDwithoutvertebralfractureandinpatientswithlowfemoralneckBMDwithor

withoutvertebralfracture.

Risedronatesodium5mgdailygivenfor3yearsincreasedbonemineraldensity(BMD)relativetocontrolatthe

lumbarspine,femoralneck,trochanterandwristandmaintainedbonedensityatthemid-shaftradius.

Inaone-yearfollow-upofftherapyafterthreeyearstreatmentwithrisedronatesodium5mgdailytherewas

rapidreversibilityofthesuppressingeffectofrisedronatesodiumonboneturnoverrate.

Bonebiopsysamplesfrompostmenopausalwomentreatedwithrisedronatesodium5mgdailyfor2to3years,

showedanexpectedmoderatedecreaseinboneturnover.Boneformedduringrisedronatesodiumtreatmentwas

ofnormallamellarstructureandbonemineralisation.Thesedatatogetherwiththedecreasedincidenceof

osteoporosisrelatedfracturesatvertebralsitesinwomenwithosteoporosisappeartoindicatenodetrimental

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Endoscopicfindingsfromanumberofpatientswithanumberofmoderatetoseveregastrointestinalcomplaintsinboth

risedronatesodiumandcontrolpatientsindicatednoevidenceoftreatmentrelatedgastric,duodenaloroesophageal

ulcersineithergroup,althoughduodenitiswasuncommonlyobservedintherisedronatesodiumgroup.

TreatmentofOsteoporosisinMen

Risedronatesodium35mgonceaweekdemonstratedefficacyinmenwithosteoporosis(agerange36to84years)ina

2-year,double-blind,placebo-controlledstudyin284patients(risedronatesodium35mgn=191).Allpatientsreceived

supplementalcalciumandvitaminD.

IncreasesinBMDwereobservedasearlyas6monthsfollowinginitiationofrisedronatesodiumtreatment.Risedronate

sodium35mgonceaweekproducedmeanincreasesinBMDatthelumbarspine,femoralneck,trochanterandtotalhip

comparedtoplaceboafter2yearsoftreatment.Antifractureefficacywasnotdemonstratedinthisstudy.

Theboneeffect(BMDincreaseandBTMdecrease)ofrisedronatesodiumissimilarinmalesandfemales.

Paediatricpopulation:Thesafetyandefficacyofrisedronatesodiumisbeinginvestigatedinanon-goingstudyof

paediatricpatientsaged4tolessthan16yearswithosteogenesisimperfecta.Aftercompletionofitsone-year

randomized,double-blind,placebocontrolledphase,astatisticallysignificantincreaseinlumbarspineBMDinthe

risedronategroupversusplacebogroupwasdemonstrated;howeveranincreasednumberofatleast1new

morphometric(identifiedbyx-ray)vertebralfracturewasfoundintherisedronategroupcomparedtoplacebo.Overall,

resultsdonotsupporttheuseofrisedronatesodiuminpaediatricpatientswithosteogenesisimperfecta.

5.2Pharmacokineticproperties

Absorption:Absorptionafteranoraldoseisrelativelyrapid(tmax~1hour)andisindependentofdoseovertherange

studied(singledosestudy,2.5to30mg;multipledosestudies,2.5to5mgdailyandupto50mgdosedweekly).Mean

oralbioavailabilityofthetabletis0.63%andisdecreasedwhenrisedronatesodiumisadministeredwithfood.

Bioavailabilitywassimilarinmenandwomen.

Distribution:Themeansteadystatevolumeofdistributionis6.3l/kginhumans.Plasmaproteinbindingisabout24%.

Metabolism:Thereisnoevidenceofsystemicmetabolismofrisedronatesodium.

Elimination:Approximatelyhalfoftheabsorbeddoseisexcretedinurinewithin24hours,and85%ofanintravenous

doseisrecoveredintheurineafter28days.Meanrenalclearanceis105ml/minandmeantotalclearanceis122

ml/min,withthedifferenceprobablyattributedtoclearanceduetoadsorptiontobone.Therenalclearanceisnot

concentrationdependent,andthereisalinearrelationshipbetweenrenalclearanceandcreatinineclearance.

Unabsorbedrisedronatesodiumiseliminatedunchangedinfaeces.Afteroraladministrationtheconcentration-time

profileshowsthreeeliminationphaseswithaterminalhalf-lifeof480hours.

SpecialPopulations

Elderly:nodosageadjustmentisnecessary.

Acetylsalicylicacid/NSAIDusers:AmongregularacetylsalicylicacidorNSAIDusers(3ormoredaysperweek)the

incidenceofuppergastrointestinaladverseeventsinrisedronatesodiumtreatedpatientswassimilartothatincontrol

patients.

5.3Preclinicalsafetydata

Intoxicologicalstudiesinratanddogdosedependentlivertoxiceffectsofrisedronatesodiumwereseen,primarilyas

enzymeincreaseswithhistologicalchangesinrat.Theclinicalrelevanceoftheseobservationsisunknown.Testicular

toxicityoccurredinratanddogatexposuresconsideredinexcessofthehumantherapeuticexposure.Doserelated

incidencesofupperairwayirritationwerefrequentlynotedinrodents.Similareffectshavebeenseenwithother

bisphosphonates.Lowerrespiratorytracteffectswerealsoseeninlongertermstudiesinrodents,althoughtheclinical

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Inreproductiontoxicitystudiesatexposuresclosetoclinicalexposureossificationchangeswereseeninsternumand/or

skulloffoetusesfromtreatedratsandhypocalcaemiaandmortalityinpregnantfemalesallowedtodeliver.Therewas

noevidenceofteratogenesisat3.2mg/kg/dayinratand10mg/kg/dayinrabbit,althoughdataareonlyavailableona

smallnumberofrabbits.Maternaltoxicitypreventedtestingofhigherdoses.Studiesongenotoxicityand

carcinogenesisdidnotshowanyparticularrisksforhumans.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

LactoseMonohydrate

MicrocrystallineCellulose

Crospovidone

MagnesiumStearate

Filmcoating:

IronOxideyellow(E172)

IronOxidered(E172)

Hypromellose

Macrogol

Hyprolose

Silicondioxide

Titaniumdioxide(E171)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

Blisterpackscontaining4tabletsinanover-labelledoutercarton.

Packsize:4tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

G&ALicensingLimited

Ballymurray

Co.Roscommon

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8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1447/4/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:5 th

September2008

10DATEOFREVISIONOFTHETEXT

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