FOSALEN ONCE WEEKLY 70MG TABLETS

Main information

  • Trade name:
  • FOSALEN ONCE WEEKLY 70MG TABLETS
  • Dosage:
  • 70 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FOSALEN ONCE WEEKLY 70MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0749/129/002
  • Authorization date:
  • 27-08-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

FosalenOnceWeekly70mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains70mgalendronicacid(assodiumalendronatetrihydrate)

Excipients:

Eachtabletcontains142.64mgoflactosemonohydrate.

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Tablet.

Whitetooff-white,ovaltablet,embossed"AN70"ononesideandtheArrowlogoontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpost-menopausalosteoporosis.

Alendronatereducestheriskofvertebralandhipfractures.

4.2Posologyandmethodofadministration

Fororaluse.

Therecommendeddoseisone70mgtabletperweek.

Toobtainsatisfactoryabsorptionofalendronate

FosalenOnceWeekly70mgtabletsmustbetakenonanemptystomachimmediatelyonrisinginthemorning,with

plainwateronly,atleast30minutesbeforethefirstfood,drinkorothermedicationoftheday.Otherdrinks(including

mineralwater),foodandsomemedicinesarelikelytoreducetheabsorptionofalendronate(seesection4.5).

Toassistdeliverytothestomachandthusreducetheriskofirritation/sideeffectslocallyandintheoesophagus(see

section4.4)

FosalenOnceWeekly70mgtabletsshouldonlybeswallowedonarisingforthedaywithawholeglassofwater(not

lessthan200mlor7fl.oz).

FosalenOnceWeeklytabletsshouldbeswallowedwhole.Thetabletsshouldnotbecrushed,chewedorallowedto

dissolveinthemouthonaccountoftheriskoforopharyngealulceration.

Patientsshouldnotliedownuntilafterthefirstmealoftheday,whichmustbeatleast30minutesaftertakingthe

tablet.

Patientsshouldnotliedownwithin30minutesoftakingFosalenOnceWeekly70mgtablets.

FosalenOnceWeekly70mgtabletsshouldnotbetakenatbedtimeorbeforearisingfortheday.

PatientsshouldreceivesupplementalcalciumandvitaminDifdietaryintakeisinadequate

Useinelderlypatients:Inclinicaltrialstherewasnoage-relateddifferencewithregardtoefficacyorsafetyprofilesof

alendronate.Thereforenoadjustmentofthedoseisnecessaryforelderlypatients.

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greaterthan35ml/min.AlendronateisnotrecommendedforpatientswithimpairedrenalfunctioniftheGFRisless

than35ml/min,asthereisnoexperienceofthis.

Useinimpairedhepaticfunction

Nodoseadjustmentisnecessary.

Useinchildren(under18years)

Alendronatesodiumisnotrecommendedforuseinchildrenundertheageof18yearsduetoinsufficientdataonsafety

andefficacyinconditionsassociatedwithpaediatricosteoporosis(alsoseesection5.1).

FosalenOnceWeekly70mgtabletshavenotbeeninvestigatedinthetreatmentofglucocorticoid-inducedosteoporosis.

Theoptimaldurationofbisphosphonatetreatmentforosteoporosishasnotbeenestablished.Theneedforcontinued

treatmentshouldbere-evaluatedperiodicallybasedonthebenefitsandpotentialrisksofalendronicacidonan

individualpatientbasis,particularlyafter5ormoreyearsofuse.

4.3Contraindications

Oesophagealabnormalitiesandotherfactorsthatdelayoesophagealemptying,suchasstrictureorachalasia.

Inabilitytostandorsituprightforatleast30minutes.

Hypersensitivitytoalendronate,otherbisphosphonatesortoanyoftheexcipients.

Hypocalcaemia.

Alsoseesection4.4.

4.4Specialwarningsandprecautionsforuse

Alendronatecancauselocalirritationtotheuppergastrointestinalmucosa.Asthereisariskofworseningofthe

underlyingdisease,cautionshouldbeobservedifalendronateisgiventopatientswithactiveuppergastrointestinal

tractproblems,suchasdysphagia,oesophagealdisease,gastritis,duodenitisorulcers,orincasesofrecent(duringthe

lastyear)severegastrointestinaldiseasesuchasgastriculcer,activegastrointestinalbleedingorsurgeryintheupper

gastrointestinaltractotherthanpyloroplasty(seesection4.3).InpatientswithknownBarrett’soesophagus,prescribers

shouldconsiderthebenefitsandpotentialrisksofalendronateonanindividualpatientbasis.

Oesophagealsideeffects(insomecasessevereandrequiringhospitalisation)suchasoesophagitis,oesophagealulcers

oroesophagealerosions,inrarecasesfollowedbyoesophagealstricture,havebeenreportedinpatientsreceiving

treatmentwithalendronate.Thephysicianshouldthereforebealerttoanysignsorsymptomsofpossibleoesophageal

reaction.Thepatientsshouldbeinstructedtodiscontinuealendronateandseekmedicalattentioniftheydevelop

symptomsofoesophagealirritationsuchasdysphagia,painonswallowing,retrosternalpainornew/worsened

heartburn.

Theriskofsevereoesophagealsideeffectsisthoughttobegreaterinpatientswhodonottakealendronatecorrectly

and/orcontinuetotakealendronateafterdevelopingsymptomsindicativeofoesophagealirritation.Itisveryimportant

thatcompleteadministrationinstructionsaregivento,andunderstood,bythepatient(seesection4.2).Patientsshould

beinformedthattheriskofoesophagealproblemsmayincreaseiftheydonotfollowtheseinstructions.

Despitenoincreasedriskhavingbeenobservedinextensiveclinicaltrials,therehavebeenpost-marketingreportsof

rarecasesofgastricandduodenalulcers,someofthemsevereandwithcomplications.Acausalrelationshipcannotbe

excluded(seesection4.8).

IfpatientsforgettotakeadoseofFosalenOnceWeekly70mgTablets,theyshouldbeinstructedtotakethetabletthe

morningaftertheyremember.

Theymustnottaketwotabletsonthesameday,butshouldreverttotakingonetabletperweek,asoriginallyscheduled

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AlendronateisnotrecommendedforpatientswithimpairedrenalfunctioniftheGFRislessthan35ml/min(see

section4.2).

Causesofosteoporosisotherthanoestrogendeficiencyandageingshouldbeconsidered.

Hypocalcaemiamustbecorrectedbeforetreatmentwithalendronateisinitiated(seesection4.3).Otherdisordersof

mineralmetabolism(suchasvitaminDdeficiencyandhypoparathyroidism)shouldalsobeeffectivelytreatedbefore

startingalendronate.Inpatientswiththeseconditionsserumcalciumandsymptomsofhypocalcaemiashouldbe

monitoredduringtreatmentwithalendronate.

Onaccountofthepositiveeffectsofalendronateontheincreaseinbonemineralisation,reductionsinserumcalcium

andserumphosphatemayoccur.Theseareusuallyslightandasymptomatic.However,inrarecasessymptomatic

hypocalcaemiahasbeenreportedwhichoccasionallyhasbeensevereandoftenoccurredinpatientswithpredisposing

conditions(e.g.hypoparathyroidism,vitaminDdeficiencyandincasesofcalciummalabsorption).

Itisthereforeparticularlyimportanttoensurethatpatientstakingglucocorticoidshaveanadequatecalciumand

vitaminDintake.

FosalenOnceWeekly70mgTabletscontainlactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,

theLapplactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimesincludingprimarilyintravenouslyadministered

bisphosphonates.Manyofthesepatientswerealsoreceivingchemotherapyandcorticosteroids.Osteonecrosisofthe

jawhasalsobeenreportedinpatientswithosteoporosisreceivingoralbisphosphonates.

Adentalexaminationwithappropriatepreventativedentistryshouldbeconsideredpriortotreatmentwith

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

poororalhygiene,periodontaldisease,smoking).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbisphosphonatetherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbisphosphonatetreatment

reducestheriskofosteonecrosisofthejaw.

Clinicaljudgementofthetreatingphysicianshouldguidethemanagementplanofeachpatientbasedonindividual

benefit/riskassessment.

Bone,joint,and/ormusclepainhasbeenreportedinpatientstakingbisphosphonates.Inpost-marketingexperience,

thesesymptomshaverarelybeensevereand/orincapacitating(seesection4.8).Thetimetoonsetofsymptomsvaried

fromonedaytoseveralmonthsafterstartingtreatment.Mostpatientshadreliefofsymptomsafterstopping.Asubset

hadrecurrenceofsymptomswhenrechallengedwiththesamedrugoranotherbisphosphonate.

Atypicalfracturesofthefemur

Atypicalsubtrochantericanddiaphysealfemoralfractureshavebeenreportedwithbisphosphonatetherapy,primarily

inpatientsreceivinglong-termtreatmentforosteoporosis.Thesetransverseorshortobliquefracturescanoccur

anywherealongthefemurfromjustbelowthelessertrochantertojustabovethesupracondylarflare.Thesefractures

occurafterminimalornotraumaandsomepatientsexperiencethighorgroinpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fracturesareoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureshasalsobeenreported.Discontinuationofbisphosphonate

therapyinpatientssuspectedtohaveanatypicalfemurfractureshouldbeconsideredpendingevaluationofthepatient,

basedonanindividualbenefitriskassessment.

Duringbisphosphonatetreatmentpatientsshouldbeadvisedtoreportanythigh,hiporgroinpainandanypatient

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PatientsshouldbeinstructedthatiftheymissadoseofFosalenOnceWeekly,theyshouldtakeonetabletonthe

morningaftertheyremember.Theyshouldnottaketwotabletsonthesamedaybutshouldreturntotakingonetablet

onceaweek,asoriginallyscheduled.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Iftakenatthesametime,itislikelythatfoodsanddrinks(includingmineralwater),calciumsupplements,antacidsand

someoralmedicineswillaffecttheabsorptionofalendronate.Patientsmustthereforewaitforatleast30minutesafter

takingalendronatebeforetakinganyotheroralmedicine(seesection4.2).

Nootherclinicallysignificantdruginteractionsareexpected.Anumberofpatientsintheclinicaltrialsreceived

oestrogen(intravaginally,transdermallyororally)concomitantlywithalendronate.Noundesirableeffectscouldbe

relatedtothecombinationtreatment.

SinceNSAIDuseisassociatedwithgastrointestinalirritation,cautionshouldbeusedduringconcomitantusewith

alendronate.

Nospecificinteractionstudieshavebeencarriedout,butalendronatewasusedinclinicaltrialsconcomitantlywitha

numberofothercommonlyprescribedmedicineswithoutanyevidenceofclinicallyunfavourableinteractions.

4.6Fertility,pregnancyandlactation

Useduringpregnancy

Thereareinsufficientdataregardingtheuseofalendronateinpregnantwomen.Animalstudiesrevealedeffectson

foetalboneformationathighdoses.Alendronategiventopregnantratscausedhypocalcaemia-relateddystocia(see

section5.3).Inviewoftheindication,alendronateshouldnotbeusedduringpregnancy.

Useduringlactation

Itisnotknownwhetheralendronateisexcretedintobreastmilkinhumans.Inviewoftheindication,alendronate

shouldnotbeusedbybreast-feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,certainadverse

reactionsthathavebeenreportedwithFosalenOnceWeekly70mgTabletsmayaffectsomepatients'abilitytodriveor

operatemachinery.IndividualresponsestoFosalenOnceWeekly70mgTabletsmayvary(seesection4.8).

4.8Undesirableeffects

Inaone-yearstudyinpost-menopausalwomenwithosteoporosistheoverallsafetyprofilesforalendronateonce-

weeklytablets(n=519)andalendronate10mgdaily(n=370)weresimilar.

Intwothree-yearstudiesofalmostidenticaldesign,withpost-menopausalwomen(alendronate10mg:n=196;placebo:

n=397)theoverallsafetyprofilesforalendronate10mgdailyandplaceboweresimilar.

Undesirableeffectsreportedbytheinvestigatorsaspossibly,probablyordefinitelyrelatedtothedrugarepresented

belowiftheyoccurredin 1%ofanyinthetreatmentgroupsintheone-yearstudyorin 1%ofthepatientswho

weretreatedwithalendronate10mgperdayandwithanincidencehigherthaninpatientswhoweretreatedwith

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Thefollowingundesirableeffectshavealsobeenreportedinclinicaltrialsand/orpostmarketing:

Nervoussystemdisorders:

Common(1/100,<1/10):Headache

Eyedisorders:

Rare(1/10,000,<1/1000):Uveitis,scleritis,episcleritis

Gastrointestinaldisorders:

Common(1/100,<1/10):Abdominalpain,dyspepsia,constipation,diarrhoea,flatulence,oesophagealulcers*,

dysphagia*,abdominaldistension,acidregurgitation.

Uncommon(1/1000,<1/100):Nausea,vomiting,gastritis,oesophagitis*oesophagealerosions*,melaena.

Rare(1/10,000,<1/1000):Oesophagealstricture*,oropharyngealulceration*,uppergastrointestinalPUB

(perforations,ulcers,bleeding),acausalrelationshipcannotberuledout.

Skinandsubcutaneoustissuedisorders:

Uncommon(1/1000,<1/100):Rash,pruritus,erythema

Rare(1/10,000,<1/1000:Rashwithphotosensitivity,urticaria,angioedema,alopecia

Veryrare(1/10,000):IsolatedcasesofsevereskinreactionsincludingStevens-Johnsonsyndromeandtoxicepidermal

necrolysishavebeenreported.

Musculoskeletal,connectivetissueandbonedisorders:

Common(1/100,<1/10):Musculoskeletalpain(bones,musclesorjoints)

Rare(1/10,000,<1/1000:Osteonecrosisofthejawhasbeenreportedinpatientstreatedbybisphosphonates.The

majorityofthereportsrefertocancerpatients,butsuchcaseshavealsobeenreportedinpatientstreatedfor

osteoporosis.Osteonecrosisofthejawisgenerallyassociatedwithtoothextractionand/orlocalinfection(including

osteomyelitis).Diagnosisofcancer,chemotherapy,radiotherapy,corticosteroidsandpoororalhygienearealsodeemed

Theone-yearstudy Three-yearstudies

Alendronateonce-

weeklytablet

(n=519)

% Alendronate

10mgdaily

(n=370)

% Alendronate

10mgdaily

(n=196)

% Placebo

(n=397)

%

Gastrointestinal

Abdominalpain 3.7 3.0 6.6 4.8

Dyspepsia 2.7 2.2 3.6 3.5

Acidregurgitation 1.9 2.4 2.0 4.3

Nausea 1.9 2.4 3.6 4.0

Abdominaldistension 1.0 1.4 1.0 0.8

Constipation 0.8 1.6 3.1 1.8

Diarrhoea 0.6 0.5 3.1 1.8

Dysphagia 0.4 0.5 1.0 0.0

Flatulence 0.4 1.6 2.6 0.5

Gastritis 0.2 1.1 0.5 1.3

Gastriculcer 0.0 1.1 0.0 0.0

Oesophagealulcer 0.0 0.0 1.5 0.0

Musculoskeletal

Musculoskeletalpain

(bone,muscleorjoints) 2.9 3.2 4.1 2.5

Musclecramps 0.2 1.1 0.0 1.0

Neurological

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Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyrare):Atypical

subtrochantericanddiaphysealfemoralfractures(bisphosphonateclassadversereaction)

Generaldisordersandadministrationsiteconditions:

Rare(1/10,000,<1/1000):Transientsymptomsasinanacutephasereaction(myalgia,malaiseandinrarecases

fever)usuallyinconnectionwiththestartoftreatment.

Metabolismandnutritiondisorders:

Rare(1/10,000,<1/1000):Symptomatichypocalcaemia,generallyinconnectionwithpredisposingconditions(see.

Section4.4).

Immunesystemdisorders:

Rare(1/10,000,<1/1000):Hypersensitivityreactionsincludingurticariaandangioedema.

*Seesection4.4andsection4.2.

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyunknown):

Nervoussystemdisorders:Dizziness,dysgeusia

Earandlabyrinthdisorders:Vertigo

Musculoskeletal,connectivetissueandbonedisorders:Jointswelling,stressfracturesoftheproximalfemoralshaft

(seesection4.4)

Generaldisordersandadministrationsiteconditions:Asthenia,peripheraloedema

Laboratoryvalues:Inclinicaltrials,asymptomatic,slightandtransientdecreasesinserumcalciumandserum

phosphatewereobservedinapprox.18and10%respectivelyofthepatientstakingalendronate10mg/dayversus12

and3%respectivelyofthosetakingplacebo.However,theincidenceofreductionsinserumcalciumto<2.0mmol/l

andserumphosphateto0.65mmol/lwascomparableinthetwogroups.

4.9Overdose

Hypocalcaemia,hypophosphataemiaanduppergastrointestinalsideeffectssuchasupsetstomach,heartburn,

oesophagitis,gastritisorulcercanoccuronoraloverdosage.Thereisnospecificinformationavailablewithregardto

overdosagewithalendronate.Milkorantacidsshouldbegiveninordertobindalendronate.Onaccountoftheriskof

oesophagealirritation,vomitingshouldnotbeinducedandthepatientshouldbekeptinanuprightposition.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Drugsaffectingbonestructureandmineralisation,bisphosphonates.

ATCcode:M05BA04

TheactivesubstanceinFosalenOnceWeekly70mgtablets,sodiumalendronatetrihydrate,isabisphosphonatethat

inhibitsosteoclasticboneresorptionwithoutanydirecteffectonboneformation.Preclinicalstudieshavedemonstrated

apreferenceforlocalisationofalendronatetositeswhereactiveresorptiontakesplace.Osteoclasticactivityis

inhibitedbutformationandbindingoftheosteoclastsisnotaffected.Boneformedduringtreatmentwithalendronate

isofnormalquality.

Treatmentofpost-menopausalosteoporosis

Osteoporosisisdefinedasbonemineraldensity(BMD)ofthespineorhip2.5standarddeviationsbelowthe

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density.

Thetherapeuticequivalenceofalendronateonce-weeklytablets(n=519)andalendronate10mgdaily(n=370)was

demonstratedinaone-yearmulticentrestudyinpost-menopausalwomenwithosteoporosis.Themeanincreasefrom

baselineofBMDinthelumbarspineafteroneyearwas5.1%(95%confidenceinterval:4.8,5.4%)inthegroup

receiving70mgonceperweekand5.4%(95%confidenceinterval:5.0,5.8%)inthegroupreceiving10mgdaily.

TheaverageincreasesinBMDinthegroupreceiving70mgonceperweekandinthegroupreceiving10mgdaily

were2.3%and2.9%inthefemoralneckand2.9%and3.1%overthetotalhip.Thetwotreatmentgroupswerealso

similarwithregardtoincreasedbonedensityinotherpartsoftheskeleton.

TheeffectsofalendronateonBMDandfractureincidenceinpost-menopausalwomenwerestudiedintwoinitial

efficacystudiesofidenticaldesign(n=994),andintheFractureInterventionTrial(FIT:n=6459).

Intheinitialefficacystudies,theincreasesinBMDwithalendronate10mgdailyrelativetoplaceboafterthreeyears

were8.8%,5.9%and7.8%atthespine,femoralneckandtrochanterrespectively.TotalbodyBMDalsoincreased

significantly.Inthepatientstreatedwithalendronate,theproportionofpatientswhosufferedoneormorevertebral

fractureswasreducedby48%(alendronate3.2%versusplacebo6.2%).Inthetwo-yearextensionsofthesestudies

theBMDinthespineandtrochantercontinuedtoincrease.Inaddition,BMDatthefemoralneckandtotalbodywas

maintained.

TheFITstudyincludedtwoplacebo-controlledtrialsinwhichalendronatewasgivendaily(5mgdailyfortwoyears

and10mgdailyforafurtheroneortwoyears).

FIT1:Athree-yearstudywith2027patientswhohadhadatleastonebaselinevertebral(compression)fracture.In

thisstudyalendronatedailyreducedtheincidenceof1newvertebralfractureby47%(alendronate7.9%versus

placebo15.0%).Inaddition,astatisticallysignificantreductionintheincidenceofhipfractureswasconfirmed

(1.1%versus2.2%,areductionof51%).

FIT2:Afour-yearstudywith4432patientswhohadalowbonemassbuthadnothadanyvertebralfractureatthe

startofthestudy.Inthisstudy,inasubgroupanalysisofosteoporoticwomen(37%ofthetotalpopulationwho

fulfilledthedefinitionofosteoporosisgivenabove)asignificantdifferencewasseenintheincidenceofhip

fractures(alendronate1.0%versusplacebo2.2%,areductionof56%)andintheincidenceof1vertebral

fracture(2.9%versus5.8%,areductionof50%).

Paediatricpatients:

Alendronatesodiumhasbeenstudiedinasmallnumberofpatientswithosteogenesisimperfectaundertheageof18

years.Resultsareinsufficienttosupporttheuseofalendronatesodiuminpaediatricpatientswithosteogenesis

imperfecta.

5.2Pharmacokineticproperties

Absorption

Comparedwithanintravenousreferencedose,themeanoralbioavailabilityofalendronateinwomenwas0.64%for

dosesrangingfrom5to70mggivenafteranovernightfastandtwohoursbeforeastandardisedbreakfast.

Bioavailabilitydecreasedtoanestimated0.46%and0.39%whenalendronatewasgivenanhourorhalfanhour

beforeastandardisedbreakfast.

Inosteoporosisstudiesalendronatewaseffectivewhenitwasgivenatleast30minutesbeforethefirstmealordrinkof

theday.Bioavailabilitywasnegligibleirrespectiveofwhetheralendronatewasgiventogetherwithoruptotwohours

afterastandardisedbreakfast.Concomitantadministrationofalendronatewithcoffeeororangejuicereduced

bioavailabilitybyapprox.60%.Inhealthypersons,oralprednisolone(20mgthreetimesdailyforfivedays)didnot

resultinanyclinicallymeaningfulchangeintheoralbioavailabilityofalendronate(ameanincreaserangingfrom20%

to44%).

Distribution

Studiesinratsshowthatalendronateisinitiallydistributedtosofttissuesafterintravenousadministrationof1mg/kg,

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exclusiveofbone,isatleast28litresinhumans.Concentrationsofdruginplasmafollowingtherapeuticoraldosesare

toolowforanalyticaldetection(<5ng/ml).Proteinbindinginhumanplasmaisapproximately78%.

Biotransformation

Thereisnoevidencethatalendronateismetabolisedinanimalsorhumans.

Elimination

Followingasingleintravenousdoseof( 14

C)alendronate,approximately50%oftheradioactivitywasexcretedinthe

urinewithin72hoursandlittleornoradioactivitywasrecoveredinthefaeces.Followingasingleintravenousdoseof

10mg,therenalclearanceofalendronatewas71ml/min,andsystemicclearancedidnotexceed200ml/min.Plasma

concentrationsfellbymorethan95%within6hoursfollowingintravenousadministration.Theterminalhalf-lifein

humansisestimatedtoexceedtenyears,reflectingreleaseofalendronatefromtheskeleton.Alendronateisnot

excretedthroughtheacidicorbasictransportsystemsofthekidneyinrats,andthusitisnotthoughttointerferewith

theexcretionofotherdrugsbythosesystemsinhumans.

Characteristicsinpatients

Preclinicalstudiesshowthatthedrugthatisnotdepositedinboneisrapidlyexcretedintheurine.Noevidenceof

saturationofboneuptakewasfoundafterchronicdosingwithcumulativeintravenousdosesupto35mg/kginanimals.

Althoughnoclinicalinformationisavailable,itislikelythat,asinanimals,eliminationofalendronateviathekidney

willbereducedinpatientswithimpairedrenalfunction.Therefore,somewhatgreateraccumulationofalendronatein

bonemightbeexpectedinpatientswithimpairedrenalfunction(seesection4.2).

5.3Preclinicalsafetydata

Conventionalstudiesofgeneraltoxicity,genotoxicityandcarcinogenicitydidnotrevealanyspecialrisksforhumans.

Studiesinfemaleratsshowedthattreatmentwithalendronateduringpregnancywasassociatedwithdystociaduring

parturition,whichwasrelatedtohypocalcaemia.Studiesinwhichratsweregivenhighdosesshowedanincreased

incidenceofincompletefoetalboneformation.Therelevanceforhumansisunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Lactosemonohydrate

Croscarmellosesodium

Magnesiumstearate

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

Thetabletsaresuppliedintriplexblister(PVC/PE/PVDC//Al)packscontaining2,4,8,12and40tablets.

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6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

TevaPharmaB.V.

Computerweg10

3542DRUtrecht

TheNetherlands

8MARKETINGAUTHORISATIONNUMBER

PA749/129/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisaton:8 th

December2006

Dateoflastrenewal:3 rd

December2009

10DATEOFREVISIONOFTHETEXT

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