ALENDRONIC ACID 10 MG TABLETS

Main information

  • Trade name:
  • ALENDRONIC ACID 10 MG TABLETS
  • Dosage:
  • 10 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALENDRONIC ACID 10 MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1390/035/001
  • Authorization date:
  • 18-02-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AlendronicAcid10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgalendronicacid(asalendronatesodium)

Excipients:Eachtabletcontains38.867mgofLactoseAnhydrous

Forafulllistofexcipientsseesection6.1

3PHARMACEUTICALFORM

Tablet

Whitetooff-white,oval,biconvextablet,debossedwith‘10’ononesideandplainonotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

4.2Posologyandmethodofadministration

Fororaluseonly.

Treatmentofpost-menopausalosteoporosis:

Therecommendeddosageis10mgoncedaily.

Treatmentofosteoporosisinmen:

Therecommendeddosageis10mgoncedaily.

Preventionofglucocorticoid-inducedosteoporosis:

Forpost-menopausalwomenwhoarenotreceivingoestrogentreatmenttherecommendeddoseisone10mgtablet

daily.Forotherpopulations,seesummaryofproductcharacteristicsforpreparationsthatcontain5mgalendronate.

ToobtainsatisfactoryabsorptionofalendronateAlendronicacidtabletsmustbetakenonanemptystomach

immediatelyonrisinginthemorning,withplainwateronly,atleast30minutesbeforethefirstfood,drinkorother

medicationoftheday.Otherdrinks(includingmineralwater),foodandsomemedicinesarelikelytoreducethe

Treatmentofpostmenopausalosteoporosis.Alendronicacidreducestheriskofvertebraland

hipfractures.

Treatmentofosteoporosisinmenatincreasedriskoffracture.Areductionintheincidenceof

vertebral,butnotofnon-vertebralfractureshasbeendemonstrated.

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Toassistdeliverytothestomachandthusreducetheriskofirritation/sideeffectslocallyandintheoesophagus(see

section4.4)

Alendronicacidtabletsshouldonlybeswallowedonrisingforthedaywithawholeglassofwater(notlessthan

200mlor7fl.oz).

Alendronicacidtabletsshouldbeswallowedwhole.Thetabletsshouldnotbechewed,suckedorallowedto

dissolveinthemouthonaccountoftheriskoforopharyngealulceration.

Patientsshouldnotliedownuntilafterthefirstmealoftheday,whichmustbeatleast30minutesaftertaking

thetablet.

Patientsshouldnotliedownwithin30minutesoftakingAlendronicacidtablets

Alendronicacidtabletsshouldnotbetakenatbedtimeorbeforearisingfortheday.

PatientsshouldbegivenacalciumandvitaminDsupplementifthedietisinadequate(seesection4.4).

Useinelderlypatients:Inclinicaltrialstherewasnoage-relateddifferencewithregardtoefficacyorsafetyprofilesof

alendronate.Thereforenoadjustmentofthedoseisnecessaryforelderlypatients.

Useinimpairedrenalfunction

Nodoseadjustmentisnecessaryinpatientswithaglomerularfiltrationrate(GFR)greaterthan35ml/min.Alendronate

isnotrecommendedforpatientswithimpairedrenalfunctioniftheGFRislessthan35ml/min,asthereisno

experienceofthis.

UseinimpairedhepaticfunctionNodoseadjustmentisnecessary.

Useinchildren(under18years):Alendronatehasbeenstudiedinasmallnumberofpatientswithosteogenesis

imperfectaunder18yearsofage.Resultsareinsufficienttosupportitsuseinchildren.

4.3Contraindications

AlendronicacidTabletiscontraindicatedin:

4.4Specialwarningsandprecautionsforuse

Alendronicacidcancauselocalirritationoftheuppergastro-intestinalmucosa.Becausethereisapotentialfor

worseningoftheunderlyingdisease,cautionshouldbeusedwhenalendronicacidisgiventopatientswithactiveupper

gastro-intestinalproblems,suchasdysphagia,oesophagealdisease,gastritis,duodenitis,orulcersorwitharecent

history(withinthepreviousyear)ofmajorgastro-intestinaldiseasesuchaspepticulcer,oractivegastro-intestinal

bleeding,orsurgeryoftheuppergastro-intestinaltractotherthanpyloroplasty(seesection4.3).Inpatientswithknown

Barrett'soesophagus,prescribersshouldconsiderthebenefitsandpotentialrisksofalendronateonanindividualpatient

basis.

Oesophagealreactions(sometimessevereandrequiringhospitalisation),suchasoesophagitis,oesophagealulcersand

oesophagealerosions,rarelyfollowedbyoesophagealstrictureorperforation,havebeenreportedinpatientsreceiving

alendronicacid.Physiciansshouldthereforebealerttoanysignsorsymptomssignallingapossibleoesophageal

reactionandpatientsshouldbeinstructedtodiscontinuealendronicacidandseekmedicalattentioniftheydevelop

symptomsofoesophagealirritationsuchasdysphagia,painonswallowingorretrosternalpain,neworworsening

Abnormalitiesoftheoesophagusandotherfactorswhichdelayoesophageal emptying

suchasstrictureorachalasia.

Inabilitytostandorsituprightforatleast30minutes.

Hypersensitivitytoalendronicacidortoanyoftheexcipient.

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Theriskofsevereoesophagealadverseexperiencesappearstobegreaterinpatientswhofailtotakealendronicacid

tabletproperlyand/orwhocontinuetotakealendronicacidtabletafterdevelopingsymptomssuggestiveof

oesophagealirritation.Itisveryimportantthatthefulldosinginstructionsareprovidedto,andunderstoodbythe

patient(seesection4.2).Patientsshouldbeinformedthatfailuretofollowtheseinstructionsmayincreasetheirriskof

oesophagealproblems.

Whilenoincreasedriskwasobservedinextensiveclinicaltrials,therehavebeenrare(post-marketing)reportsof

gastricandduodenalulcers,somesevereandwithcomplications.Howeveracausalrelationshiphasnotbeen

established.

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimensincludingprimarilyintravenouslyadministered

bisphosphonates.Manyofthesepatientswerealsoreceivingchemotherapyandcorticosteroids.Osteonecrosisofthe

jawhasalsobeenreportedinpatientswithosteoporosisreceivingoralbisphosphonates.

Adentalexaminationwithappropriatepreventivedentistryshouldbeconsideredpriortotreatmentwith

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

poororalhygiene,periodontaldisease).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbisphosphonatetherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbisphosphonatetreatment

reducestheriskofosteonecrosisofthejaw.

Clinicaljudgementofthetreatingphysicianshouldguidethemanagementplanofeachpatientbasedonindividual

benefit/riskassessment.

Stressfractures(alsoknownasinsufficiencyfractures)oftheproximalfemoralshafthavebeenreportedinpatients

treatedlong-termwithalendronicacid(timetoonsetinthemajorityofcasesrangedfrom18monthsto10years).The

fracturesoccurredafterminimalornotraumaandsomepatientsexperiencedthighpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fractureswereoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureswasalsoreported.Discontinuationofbisphosphonatetherapyin

patientswithstressfractureisadvisablependingevaluationofthepatient,basedonanindividualbenefitrisk

assessment.

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

thesesymptomshaverarelybeensevereand/orincapacitating(seesection4.8).Thetimetoonsetofsymptomsvaried

fromonedaytoseveralmonthsafterstartingtreatment.Mostpatientshadreliefofsymptomsafterstopping.Asubset

hadrecurrenceofsymptomswhenrechallengedwiththesamedrugoranotherbisphosphonate.

AlendronicacidTabletisnotrecommendedforpatientswithrenalimpairmentwhereGFRislessthan35ml/min,(see

section4.2).Causesofosteoporosisotherthanoestrogendeficiency,ageingandglucocorticoiduseshouldbe

considered.

Hypocalcaemiamustbecorrectedbeforeinitiatingtherapywithalendronicacid(seesection4.3).Otherdisorders

affectingmineralmetabolism(suchasvitaminDdeficiencyandhypoparathyroidism)shouldalsobeeffectivelytreated.

Inpatientswiththeseconditions,serumcalciumandsymptomsofhypocalcaemiashouldbemonitoredduringtherapy

withalendronicacid.

Duetothepositiveeffectsofalendronicacidinincreasingbonemineral,decreasesinserumcalciumandphosphate

mayoccur,especiallyinpatientstakingglucocorticoids,inwhomcalciumabsorptionmaybedecreased.Theseare

usuallysmallandasymptomatic.However,therehavebeenrarereportsofsymptomatichypocalcaemia,whichhave

occasionallybeensevereandoftenoccurredinpatientswithpredisposingconditions(e.g.hypoparathyroidism,vitamin

Ddeficiencyandcalciummalabsorption).

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Excipients

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Iftakenatthesametime,itislikelythatcalciumsupplements,antacids,andsomeoralmedicationswillinterferewith

absorptionofalendronicacid.Therefore,patientsmustwaitatleast30minutesaftertakingalendronicacidtablet

beforetakinganyotheroralmedication.

Nootherdruginteractionsofclinicalsignificanceareanticipated.ConcomitantuseofHRT(oestrogen±progestin)and

alendronicacidtabletwasassessedintwoclinicalstudiesofoneortwoyearsdurationinpost-menopausalosteoporotic

women(5.1).Anumberofpatientsintheclinicaltrialsreceivedoestrogen(intravaginal,transdermal,ororal)while

takingalendronicacid.Noadverseexperiencesattributabletotheirconcomitantusewereidentified.

SinceNSAIDuseisassociatedwithgastrointestinalirritation,cautionshouldbeusedduringconcomitantusewith

alendronate.

Althoughspecificinteractionstudieswerenotperformed,inclinicalstudiesalendronicacidwasusedconcomitantly

withawiderangeofcommonlyprescribeddrugswithoutevidenceofclinicaladverseinteractions.

4.6Fertility,pregnancyandlactation

Useduringpregnancy

Therearenoadequatedatafromtheuseofalendronicacidinpregnantwomen.Animalstudiesdonotindicatedirect

harmfuleffectswithrespecttopregnancy,embryonal/fetaldevelopment,orpostnataldevelopment.Alendronicacid

givenduringpregnancyinratscauseddystociarelatedtohypocalcemia(seesection5.3).Giventheindication,

alendronicacidshouldnotbeusedduringpregnancy.

Useduringlactation

Itisnotknownwhetheralendronicacidtabletisexcretedintohumanbreastmilk.Giventheindication,alendronic

acidshouldnotbeusedbybreast-feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Alendronicacidtablethasnoeffectsonabilitytodriveandusemachines.Nostudiesontheeffectsontheabilityto

driveandusemachineshavebeenperformed.However,certainadversereactionsthathavebeenreportedwith

'alendronicacid'mayaffectsomepatients'abilitytodriveoroperatemachinery.Individualresponsesto'alendronic

acid'mayvary(seesection4.8).

4.8Undesirableeffects

Inaone-yearstudyinpost-menopausalwomenwithosteoporosistheoverallsafetyprofilesofAlendronicacid70mg

(n=519)andalendronicacid10mg/day(n=370)weresimilar.

Intwothree-yearstudiesofvirtuallyidenticaldesign,inpost-menopausalwomen(alendronicacid10mg:n=196,

placebo:n=397)theoverallsafetyprofilesofalendronicacidtablet10mg/dayandplaceboweresimilar.

Adverseexperiencesreportedbytheinvestigatorsaspossibly,probablyordefinitelydrug-relatedarepresentedbelow

iftheyoccurredin 1%ineithertreatmentgroupintheone-yearstudy,orin 1%ofpatientstreatedwithalendronic

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Thefollowingadverseexperienceshavealsobeenreportedduringclinicalstudiesand/orpost-marketinguse:

[Common(1/100,<1/10),Uncommon(1/1000,<1/100),Rare(1/10,000,<1/1000),Veryrare(<1/10,000not

One-YearStudy Three-YearStudies

Alendronic

Acid

OnceWeekly

70mg

(n=519) % Alendronic

Acid

10mg/day

(n=370)% Alendronic

Acid

10mg/day

(n=196)% Placebo

(n=397)%

Gastro-intestinal

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

abdominaldistention 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

musculoskeletal

(bone,muscleorjoint)

pain 2.9 3.2 4.1 2.5

musclecramp 0.2 1.1 0.0 1.0

Neurological

headache 0.4 0.3 2.6 1.5

Immunesystemdisorders:

Rare: hypersensitivityreactionsincludingurticariaandangioedema

Metabolismandnutritiondisorders:

Rare: symptomatichypocalcaemia,ofteninassociationwithpredisposing

conditions.(seesection4.4)

Nervoussystemdisorders:

Common: headache

Eyedisorders:

Rare: uveitis,scleritis,episcleritis

Gastro-intestinaldisorders:

Common: abdominalpain,dyspepsia,constipation,diarrhoea,flatulence,

oesophagealulcer*,dysphagia*,abdominaldistension,acidregurgitation

Uncommon: nausea,vomiting,gastritis,oesophagitis*,oesophagealerosions*,melena

Rare: oesophagealstricture*,oropharyngealulceration*,uppergastro-

intestinalPUBs(perforation,ulcers,bleeding)(seesection4.4)

*Seesections4.2and4.4

Skinandsubcutaneoustissuedisorders:

Uncommon: rash,pruritus,erythema

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Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyunknown):

Nervoussystemdisorders:dizziness,dysgeusia

Earandlabyrinthdisorders:vertigo

Skinandsubcutaneoustissuedisorders:alpoecia

Musculoskeletal,connectivetissueandbonedisorders:jointswelling,stressfracturesoftheproximalshaft(see

section4.4)

Generaldisordersandadministrationsiteconditions:asthenia,peripheraloedema

Laboratorytestfindings

Inclinicalstudies,asymptomatic,mildandtransientdecreasesinserumcalciumandphosphatewereobservedin

approximately18and10%,respectively,ofpatientstakingalendronicacidtablet10mg/dayversusapproximately12

and3%ofthosetakingplacebo.However,theincidencesofdecreasesinserumcalciumto<8.0mg/dl(2.0mmol/l)and

serumphosphateto 2.0mg/dl(0.65mmol/l)weresimilarinbothtreatmentgroups.

4.9Overdose

NospecificinformationisavailableonthetreatmentofoverdosagewithAlendronicacid.Hypocalcaemia,

hypophosphataemiaanduppergastro-intestinaladverseevents,suchasupsetstomach,heartburn,oesophagitis,

gastritis,orulcer,mayresultfromoraloverdosage.Milkorantacidsshouldbegiventobindalendronicacid.Owingto

theriskofoesophagealirritation,vomitingshouldnotbeinducedandthepatientshouldremainfullyupright.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Drugsaffectingbonestructureandmineralisation,bisphosphonates

ATCcode:M05BA04

Alendronicacidisabisphosphonatethatinhibitsosteoclasticboneresorptionwithnodirecteffectonboneformation.

Veryrareandisolated

cases: isolatedcasesofsevereskinreactionsincludingStevens-Johnson

syndromeandtoxicepidermalnecrolysis

Musculoskeletal,connectivetissueandbonedisorders:

Common: musculoskeletal(bone,muscleorjoint)pain

Rare: Osteonecrosisofthejawhasbeenreportedinpatientstreatedby

bisphosphonates.Themajorityofthereportsrefertocancerpatients,but

suchcaseshavealsobeenreportedinpatientstreatedforosterporosis.

Osteonecrosisofthejawisgenerallyassociatedwithtoothextraction

and/orlocalinfection(includingosteomyelitis).Diagnosisofcancer,

chemotherapy,radiotherapy,corticosteroidsandpoororalhygienealso

deemedasriskfactors,severemusculoskeletal(bone,muscleorjoint)

pain(seeSection4.4'Specialwarningsandprecautionsforuse')

Generaldisordersandadministrationsiteconditions:

Rare: transientsymptomsasinanacute-phaseresponse(myalgia,malaiseand

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Treatmentofpost-menopausalosteoporosis

Theeffectsofalendronicacidonbonemassandfractureincidenceinpost-menopausalwomenwereexaminedintwo

initialefficacystudiesofidenticaldesign(n=994)aswellasintheFractureInterventionTrial(FIT:n=6,459).

Intheinitialefficacystudies,themeanbonemineraldensity(BMD)increaseswithalendronicacid10mg/dayrelative

toplaceboatthreeyearswere8.8%,5.9%and7.8%atthespine,femoralneckandtrochanter,respectively.Totalbody

BMDalsoincreasedsignificantly.Therewasa48%reductionintheproportionofpatientstreatedwithalendronicacid

experiencingoneormorevertebralfracturesrelativetothosetreatedwithplacebo.Inthetwo-yearextensionofthese

studiesBMDatthespineandtrochantercontinuedtoincreaseandBMDatthefemoralneckandtotalbodywere

maintained.

FITconsistedoftwoplacebo-controlledstudies:athree-yearstudyof2,027patientswhohadatleastonebaseline

vertebral(compression)fractureandafour-yearstudyof4,432patientswithlowbonemassbutwithoutabaseline

vertebralfracture,37%ofwhomhadosteoporosisasdefinedbyabaselinefemoralneckBMDatleast2.5standard

deviationsbelowthemeanforyoung,adultwomen.InallFITpatientswithosteoporosisfrombothstudies,alendronic

acidreducedtheincidenceof: 1vertebralfractureby48%,multiplevertebralfracturesby87%,1painfulvertebral

fractureby45%,anypainfulfractureby31%andhipfractureby54%.

Overalltheseresultsdemonstratetheconsistenteffectofalendronicacidtoreducetheincidenceoffractures,including

thoseofthespineandhip,whicharethesitesofosteoporoticfractureassociatedwiththegreatestmorbidity.

Concomitantusewithoestrogen/hormonereplacementtherapy(HRT)

TheeffectsonBMDoftreatmentwithalendronicacidtablet10mgonce-dailyandconjugatedoestrogen(0.625

mg/day)eitheraloneorincombinationwereassessedinatwo-yearstudyofhysterectomised,post-menopausal,

osteoporoticwomen.Attwoyears,theincreasesinlumbarspineBMDfrombaselineweresignificantlygreaterwith

thecombination(8.3%)thanwitheitheroestrogenoralendronicacidtabletalone(both6.0%).

TheeffectsonBMDwhenalendronicacidtabletwasaddedtostabledoses(foratleastoneyear)ofHRT(oestrogen±

progestin)wereassessedinaone-yearstudyinpost-menopausal,osteoporoticwomen.Theadditionofalendronicacid

tablet10mgonce-dailytoHRTproduced,atoneyear,significantlygreaterincreasesinlumbarspineBMD(3.7%)vs.

HRTalone(1.1%).Inthesestudies,significantincreasesorfavourabletrendsinBMDforcombinedtherapycompared

withHRTalonewereseenatthetotalhip,femoralneckandtrochanter.Nosignificanteffectwasseenfortotalbody

BMD.

Treatmentofosteoporosisinmen

Theefficacyofalendronicacidtablet10mgoncedailyinmen(ages31to87;mean,63)withosteoporosiswas

demonstratedinatwo-yearstudy.Attwoyears,themeanincreasesrelativetoplaceboinBMDinmenreceiving

alendronicacidtablet10mg/daywere:lumbarspine,5.3%;femoralneck,2.6%;trochanter,3.1%;andtotalbody,

1.6%.Alendronicacidtabletwaseffectiveregardlessofage,race,gonadalfunction,baselinerateofboneturnover,or

baselineBMD.Consistentwithmuchlargerstudiesinpost-menopausalwomen,inthese127men,alendronicacid

tablet10mg/dayreducedtheincidenceofnewvertebralfracture(assessedbyquantitativeradiography)relativeto

placebo(0.8%vs.7.1%)and,correspondingly,alsoreducedheightloss(-0.6vs.-2.4mm).

Glucocorticoid-inducedosteoporosis

Theefficacyofalendronicacidtablet5and10mgoncedailyinmenandwomenreceivingatleast7.5mg/dayof

prednisone(orequivalent)wasdemonstratedintwostudies.Attwoyearsoftreatment,spineBMDincreasedby3.7%

and5.0%(relativetoplacebo)withalendronicacidtablet5and10mg/dayrespectively.SignificantincreasesinBMD

werealsoobservedatthefemoralneck,trochanter,andtotalbody.Inpost-menopausalwomennotreceivingoestrogen,

greaterincreasesinlumbarspineandtrochanterBMDwereseeninthosereceiving10mgalendronicacidtabletthan

thosereceiving5mg.Alendronicacidtabletwaseffectiveregardlessofdoseordurationofglucocorticoiduse.Data

pooledfromthreedosagegroups(5or10mgfortwoyearsor2.5mgforoneyearfollowedby10mgforoneyear)

showedasignificantreductionintheincidenceofpatientswithanewvertebralfractureattwoyears(Alendronicacid

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5.2Pharmacokineticproperties

Absorption

Relativetoanintravenous(IV)referencedose,theoralbioavailabilityofalendronicacidtabletinwomenwas0.7%for

dosesrangingfrom5to40mgwhenadministeredafteranovernightfastandtwohoursbeforeastandardisedbreakfast.

Oralbioavailabilityinmen(0.6%)wassimilartothatinwomen.Bioavailabilitywasdecreasedsimilarlytoan

estimated0.46%and0.39%whenalendronicacidtabletwasadministeredonehourorhalfanhourbeforea

standardisedbreakfast.Inosteoporosisstudies,alendronicacidtabletwaseffectivewhenadministeredatleast30

minutesbeforethefirstfoodorbeverageoftheday.

Bioavailabilitywasnegligiblewhetheralendronicacidtabletwasadministeredwith,oruptotwohoursafter,a

standardisedbreakfast.Concomitantadministrationofalendronicacidwithcoffeeororangejuicereduced

bioavailabilitybyapproximately60%.

Inhealthysubjects,oralprednisone(20mgthreetimesdailyforfivedays)didnotproduceaclinicallymeaningful

changeinoralbioavailabilityofalendronicacid(ameanincreaserangingfrom20%to44%).

Distribution

Studiesinratsshowthatalendronicacidtablettransientlydistributestosofttissuesfollowing1mg/kgIV

administrationbutisthenrapidlyredistributedtoboneorexcretedintheurine.Themeansteady-statevolumeof

distribution,exclusiveofbone,isatleast28litresinhumans.Concentrationsofdruginplasmafollowingtherapeutic

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

Biotransformation

Thereisnoevidencethatalendronicacidismetabolisedinanimalsorhumans.

Elimination

FollowingasingleIVdoseof[ 14

C]alendronicacidtablet,approximately50%oftheradioactivitywasexcretedinthe

urinewithin72hoursandlittleornoradioactivitywasrecoveredinthefaeces.Followingasingle10mgIVdose,the

renalclearanceofalendronicacidtabletwas71ml/min,andsystemicclearancedidnotexceed200ml/min.Plasma

concentrationsfellbymorethan95%withinsixhoursfollowingIVadministration.Theterminalhalf-lifeinhumansis

estimatedtoexceedtenyears,reflectingreleaseofalendronicacidfromtheskeleton.Alendronicacidtabletisnot

excretedthroughtheacidicorbasictransportsystemsofthekidneyinrats,andthusitisnotanticipatedtointerfere

withtheexcretionofotherdrugsbythosesystemsinhumans.

Characteristicsinpatients

Preclinicalstudiesshowthatthedrugthatisnotdepositedinboneisrapidlyexcretedintheurine.Noevidenceof

saturationofboneuptakewasfoundafterchronicdosingwithcumulativeIVdosesupto35mg/kginanimals.

Althoughnoclinicalinformationisavailable,itislikelythat,asinanimals,eliminationofalendronicacidviathe

kidneywillbereducedinpatientswithimpairedrenalfunction.Therefore,somewhatgreateraccumulationof

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5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityandcarcinogenicpotential.Studiesinfemaleratshaveshownthattreatmentwithalendronic

acidduringpregnancywasassociatedwithdystociaindamsduringparturitionwhichwasrelatedtohypocalcaemia.In

studies,ratsgivenhighdosesshowedanincreasedincidenceofincompletefetalossification.Therelevancetohumans

isunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Lactoseanhydrous

Cellulosemicrocrystalline(E460)

Croscarmellosesodium

Magnesiumstearate

6.2Incompatibilities

Notapplicable

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions

6.5Natureandcontentsofcontainer

OpaquewhitePVC/ALUblister

Packsize:14tablets,28tablets,30tablets,50tablets,56tablets,84tablets,90tablets,98tablets,112tabletsor140

tablets.

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Anyunusedproductorwastematerialshouldbedisposedofinaccordancewithlocalrequirements.

7MARKETINGAUTHORISATIONHOLDER

AccordHealthcareLimited

SageHouse

319,PinnerRoad

NorthHarrow

MiddlesexHA14HF

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:18thFebruary2011

10DATEOFREVISIONOFTHETEXT

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