ACTONEL 5 MG FILM-COATED TABLETS

Main information

  • Trade name:
  • ACTONEL 5 MG FILM-COATED TABLETS
  • Dosage:
  • 5 Milligram
  • Pharmaceutical form:
  • Film Coated Tablet
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ACTONEL 5 MG FILM-COATED TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA0465/165/002
  • Authorization date:
  • 12-01-2007
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Actonel5mgfilm-coatedtablets.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachfilm-coatedtabletcontains5mgrisedronatesodium(equivalentto4.64mgrisedronicacid).

ExcipientsincludeLactosemonohydrate.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coatedtablet.

ProductimportedfromItaly

Ovalyellowfilm-coatedtabletwith'RSN'ononesideand'5mg'ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpostmenopausalosteoporosis,toreducetheriskofvertebralfractures.Treatmentofestablished

postmenopausalosteoporosis,toreducetheriskofhipfractures.Preventionofosteoporosisinpostmenopausalwomen

withincreasedriskofosteoporosis(seesection5.1).

Tomaintainorincreasebonemassinpostmenopausalwomenundergoinglong-term(morethan3months),systemic

corticosteroidtreatmentatdoses ≥7.5mg/dayprednisoneorequivalent.

4.2Posologyandmethodofadministration

Therecommendeddailydoseinadultsisone5mgtabletorally.TheabsorptionofActonelisaffectedbyfood,thusto

ensureadequateabsorptionpatientsshouldtakeActonel:

Beforebreakfast:Atleast30minutesbeforethefirstfood,othermedicinalproductordrink(otherthanplainwater)of

theday.

Intheparticularinstancethatbeforebreakfastdosingisnotpractical,Actonelcanbetakenbetweenmealsorinthe

eveningatthesametimeeveryday,withstrictadherencetothefollowinginstructions,toensureActonelistakenonan

emptystomach:

Betweenmeals:Actonelshouldbetakenatleast2hoursbeforeandatleast2hoursafteranyfood,medicinalproduct

ordrink(otherthanplainwater).

Intheevening:Actonelshouldbetakenatleast2hoursafterthelastfood,medicinalproductordrink(otherthan

plainwater)oftheday.Actonelshouldbetakenatleast30minutesbeforegoingtobed.

Ifanoccasionaldoseismissed,Actonelcanbetakenbeforebreakfast,betweenmeals,orintheeveningaccordingto

theinstructionsabove.

Thetabletsmustbeswallowedwholeandnotsuckedorchewed.ToaiddeliveryofthetablettothestomachActonelis

tobetakenwhileinanuprightpositionwithaglassofplainwater(>120ml).Patientsshouldnotliedownfor30

minutesaftertakingthetablet(seesection4.4).

SupplementalcalciumandvitaminDshouldbeconsideredifthedietaryintakeisinadequate.

Elderly:Nodosageadjustmentisnecessarysincebioavailability,distributionandeliminationweresimilarinelderly

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Children:SafetyandefficacyofActonelhavenotbeenestablishedinchildrenandadolescents.

4.3Contraindications

Knownhypersensitivitytorisedronatesodiumortoanyofitsexcipients.

Hypocalcaemia(seesection4.4).

Pregnancyandlactation.

Severerenalimpairment(creatinineclearance<30ml/min).

4.4Specialwarningsandprecautionsforuse

Foods,drinks(otherthanplainwater)andmedicinalproductscontainingpolyvalentcations(suchascalcium,

magnesium,ironandaluminium)interferewiththeabsorptionofbisphosphonatesandshouldnotbetakenatthesame

timeasActonel(seesection4.5).Inordertoachievetheintendedefficacy,strictadherencetodosingrecommendations

isnecessary(seesection4.2)

Efficacyofbisphosphonatesinthetreatmentofpostmenopausalosteoporosisisrelatedtothepresenceoflowbone

mineraldensity(BMDT-scoreathiporlumbarspine<-2.5SD)and/orprevalentfracture.

Highageorclinicalriskfactorsforfracturealonearenotreasonstoinitiatetreatmentofosteoporosiswitha

bisphosphonate.

TheevidencetosupportefficacyofbisphosphonatesincludingActonelinveryelderlywomen>80years)islimited

(seesection5.1).

Somebisphosphonateshavebeenassociatedwithoesophagitisandoesophagealulcerations.Thereforepatientsshould

payattentiontothedosinginstructions(seesection4.2).Inpatientswhohaveahistoryofoesophagealdisorderswhich

delayoesophagealtransitoremptyinge.g.strictureorachalasia,orwhoareunabletostayintheuprightpositionforat

least30minutesaftertakingthetablet,risedronatesodiumshouldbeusedwithspecialcautionbecauseoflimited

clinicalexperienceinthesepatients.Prescribersshouldemphasisetheimportanceofthedosinginstructionstothese

patients.

HypocalcaemiashouldbetreatedbeforestartingActoneltherapy.Otherdisturbancesofboneandmineralmetabolism

(e.g.parathyroiddysfunction,hypovitaminosisD)shouldbetreatedatthetimeofstartingActoneltherapy.

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimensincludingprimarilyintravenouslyadministeredby

biphosphates.Manyofthesepatientswerealsoreceivingchemotherapyandcorticosteroids.Osteonecrosisofthejaw

hasalsobeenreportedinpatientswithosteoporosisreceivingoralbiphosphonates.

Adentalexaminationwithappropriatepreventivedentistryshouldbeconsideredpriortotreatmentwith

biphosphonatesinpatientswithconcomitantriskfactors(e.g.cancer,chemotherapy,radiotherapy,corticosteroids,poor

oralhygiene).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbiphosphonatetherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbiphosphonatetreatment

reducestheriskofosteonecrosisofthejaw

Clinicaljudgementofthetreatingphysicianshouldguidethemanagementplanofeachpatientbasedonindividual

benefit/riskassessment.

Thismedicinecontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactase

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Noformalinteractionstudieshavebeenperformed,howevernoclinicallyrelevantinteractionswithothermedicinal

productswerefoundduringclinicaltrials.IntheActonelPhaseIIIosteoporosisstudies,acetylsalicylicacidorNSAID

usewasreportedby33%and45%ofpatientsrespectively.

IfconsideredappropriateActonelmaybeusedconcomitantlywithoestrogensupplementation.

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

willinterferewiththeabsorptionofActonel(seesection4.4).

Actonelisnotsystemicallymetabolised,doesnotinducecytochromeP450enzymes,andhaslowproteinbinding.

4.6Fertility,pregnancyandlactation

Therearenoadequatedatafromtheuseofrisedronatesodiuminpregnantwomen.Studiesinanimalshaveshown

reproductivetoxicity(seesection5.3).Thepotentialriskforhumansisunknown.Actonelmustnotbeusedduring

pregnancyorbybreast-feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

RisedronatehasbeenstudiedinphaseIIIclinicaltrialsinvolvingmorethan15,000patients.Themajorityof

undesirableeffectsobservedinclinicaltrialsweremildtomoderateinseverityandusuallydidnotrequirecessationof

therapy.

AdverseexperiencesreportedinphaseIIIclinicaltrialsinpostmenopausalwomenwithosteoporosistreatedforupto

36monthswithrisedronate5mg/day(n=5020)orplacebo(n=5048)andconsideredpossiblyorprobablyrelatedto

risedronatearelistedbelowusingthefollowingconvention(incidencesversusplaceboareshowninbrackets):very

common( ≥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:

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Investigations(hepatobiliary):

Rare:abnormalliverfunctiontests*

Laboratoryfindings:Early,transient,asymptomaticandmilddecreasesinserumcalciumandphosphatelevelshave

beenobservedinsomepatients.

Thefollowingadditionaladversereactionshavebeenreportedduringpost-marketinguse(frequencyunknown):

Eyedisorders:

Iritis,uveitis

Musculoskeletalandconnectivetissuedisorders:

Osteonecrosisofthejaw

Skinandsubcutaneoustissuedisorders:

Hypersensitivityandskinreactions,includingangioedema,generalisedrash,andbullousskinreactions,somesevere.

*NorelevantincidencesfromPhaseIIIosteoporosisstudies;frequencybasedonadverseevent/laboratory/rechallenge

findingsinearliertrials.

4.9Overdose

Nospecificinformationisavailableonthetreatmentofoverdosewithrisedronatesodium.

Decreasesinserumcalciumfollowingsubstantialoverdosemaybeexpected.Signsandsymptomsofhypocalcaemia

mayalsooccurinsomeofthesepatients.

Milkorantacidscontainingmagnesium,calciumoraluminiumshouldbegiventobindrisedronateandreduce

absorptionoftherisedronatesodium.Incasesofsubstantialoverdose,gastriclavagemaybeconsideredtoremove

unabsorbedrisedronatesodium.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmaco-therapeuticgroup:Bisphosphonates

ATCCode:M05BA07

Risedronatesodiumisapyridinylbisphosphonatethatbindstobonehydroxyapatiteandinhibitsosteoclast-mediated

boneresorption.Theboneturnoverisreducedwhiletheosteoblastactivityandbonemineralisationispreserved.In

preclinicalstudiesrisedronatesodiumdemonstratedpotentanti-osteoclastandantiresorptiveactivity,anddose

dependentlyincreasedbonemassandbiomechanicalskeletalstrength.Theactivityofrisedronatesodiumwas

confirmedbymeasuringbiochemicalmarkersforboneturnoverduringpharmacodynamicandclinicalstudies.

Decreasesinbiochemicalmarkersofboneturnoverwereobservedwithin1monthandreachedamaximumin3-6

months.

TreatmentandPreventionofPostmenopausalOsteoporosis:

Anumberofriskfactorsareassociatedwithpostmenopausalosteoporosisincludinglowbonemass,lowbonemineral

density,earlymenopause,ahistoryofsmokingandafamilyhistoryofosteoporosis.Theclinicalconsequenceof

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Theclinicalprogrammestudiedtheeffectofrisedronatesodiumontheriskofhipandvertebralfracturesandcontained

earlyandlatepostmenopausalwomenwithandwithoutfracture.Dailydosesof2.5mgand5mgwerestudiedandall

groups,includingthecontrolgroups,receivedcalciumandvitaminD(ifbaselinelevelswerelow).Theabsoluteand

relativeriskofnewvertebralandhipfractureswereestimatedbyuseofatime-to-firsteventanalysis.

Twoplacebo-controlledtrials(n=3,661)enrolledpostmenopausalwomenunder85yearswithvertebralfracturesat

baseline.Risedronatesodium5mgdailygivenfor3yearsreducedtheriskofnewvertebralfracturesrelativetothe

controlgroup.Inwomenwithrespectivelyatleast2oratleast1vertebralfractures,therelativeriskreductionwas49%

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

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

Benefitswerealsodemonstratedinwomenwithmultiplefracturesatbaseline.Risedronatesodium5mgdailyalso

reducedtheyearlyheightlosscomparedtothecontrolgroup.

Twofurtherplacebocontrolledtrialsenrolledpostmenopausalwomenabove70yearswithorwithoutvertebral

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

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

thebasisofatleastonenon-skeletalriskfactorforhipfractureorlowbonemineraldensityatthefemoralneck.

Statisticalsignificanceoftheefficacyofrisedronatesodiumversusplaceboisonlyreachedwhenthetwotreatment

groups2.5mgand5mgarepooled.Thefollowingresultsareonlybasedona-posteriorianalysisofsubgroupsdefined

byclinicalpractiseandcurrentdefinitionsofosteoporosis:

-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)

relativetocontrolatthelumbarspine,femoralneck,trochanterandwristandpreventedbonelossatthemid-shaft

radius.

Inaone-yearfollow-upofftherapyafterthreeyearstreatmentwithrisedronatesodium5mgdailytherewasrapid

reversibilityofthesuppressingeffectofrisedronatesodiumonboneturnoverrate.

Inpostmenopausalwomentakingoestrogen,risedronatesodium5mgdailyincreasedbonemineraldensity(BMD)at

thefemoralneckandmid-shaftradiusonly,comparedtooestrogenalone.

Bonebiopsysamplesfrompostmenopausalwomentreatedwithrisedronatesodium5mgdailyfor2to3years,

showedanexpectedmoderatedecreaseinboneturnover.Boneformedduringrisedronatesodiumtreatmentwasof

normallamellarstructureandbonemineralisation.Thesedatatogetherwiththedecreasedincidenceofosteoporosis

relatedfracturesatvertebralsitesinwomenwithosteoporosisappeartoindicatenodetrimentaleffectonbonequality.

Endoscopicfindingsfromanumberofpatientswithanumberofmoderatetoseveregastrointestinalcomplaintsin

bothrisedronatesodiumandcontrolpatientsindicatednoevidenceoftreatmentrelatedgastric,duodenalor

oesophagealulcersineithergroup,althoughduodenitiswasuncommonlyobservedintherisedronatesodiumgroup.

Inatrialcomparingbefore-breakfastdosinganddosingatothertimesofthedayinwomenwithpostmenopausal

osteoporosis,lumbarspineBMDgainswerestatisticallyhigherwithbefore-breakfastdosing.

CorticosteroidInducedOsteoporosis:

Theclinicalprogrammeincludedpatientsinitiatingcorticosteroidtherapy(>7.5mg/dayprednisoneorequivalent)

withintheprevious3monthsorpatientswhohadbeentakingcorticosteroidsformorethan6months.Resultsofthese

studiesdemonstratethat:

Risedronatesodium5mgdailygivenforoneyearmaintainsorincreasesbonemineraldensity(BMD)relativeto

controlatthelumbarspine,femoralneck,andtrochanter.

Risedronatesodium5mgdailyreducedtheincidenceofvertebralfractures,monitoredforsafety,relativetocontrolat

1yearinpooledstudies.

histologicalexaminationofbonebiopsiesfrompatientstakingcorticosteroidsandrisedronatesodium5mgdailydid

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5.2Pharmacokineticproperties

Absorption:Absorptionafteranoraldoseisrelativelyrapid(t

~1hour)andisindependentofdoseovertherange

studied(2.5to30mg).Meanoralbioavailabilityofthetabletis0.63%andisdecreasedwhenrisedronatesodiumis

administeredwithfood.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

incidenceofuppergastrointestinaladverseeventsinActoneltreatedpatientswassimilartothatincontrolpatients.

5.3Preclinicalsafetydata

Intoxicologicalstudiesinratanddogdosedependentlivertoxiceffectsofrisedronatesodiumwereseen,primarilyas

enzymeincreaseswithhistologicalchangesinrat.Theclinicalrelevanceoftheseobservationsisunknown.Testicular

toxicityoccurredinratanddogatexposuresconsideredinexcessofthehumantherapeuticexposure.Doserelated

incidencesofupperairwayirritationwerefrequentlynotedinrodents.Similareffectshavebeenseenwithother

bisphosphonates.Lowerrespiratorytracteffectswerealsoseeninlongertermstudiesinrodents,althoughtheclinical

significanceofthesefindingsisunclear.Inreproductiontoxicitystudiesatexposuresclosetoclinicalexposure

ossificationchangeswereseeninsternumand/orskulloffoetusesfromtreatedratsandhypocalcemiaandmortalityin

pregnantfemalesallowedtodeliver.

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

availableonasmallnumberofrabbits.Maternaltoxicitypreventedtestingofhigherdoses.Studiesongenotoxicityand

carcinogenesisdidnotshowanyparticularrisksforhumans.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Microcrystallinecellulose

Crospovidone

Magnesiumstearate

Filmcoating:

Ferricoxideyellow(E172)

Hypromellose

Macrogol400

Hyprolose

Macrogol8000

Silicondioxide

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6.2Incompatibilities

Notapplicable

6.3Shelflife

Theshelf-lifeexpirydateofthisproductisthedateshownonthecontainerandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Nospecialstorageconditions

6.5Natureandcontentsofcontainer

Blisterpacksof28tabletscontainedinanoutercardboardcarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

PCOManufacturing

Unit10,AshbourneBusinessPark

Rath

Ashbourne

Co.Meath

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA465/165/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation12 th

January2007

10DATEOFREVISIONOFTHETEXT

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