ALENDRONIC ACID CEFT

Main information

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

Documents

Localization

  • Available in:
  • ALENDRONIC ACID CEFT
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1524/002/001
  • Authorization date:
  • 07-10-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AlendronicAcidCeft10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgalendronicacid(assodiumalendronate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet

Whitetooff-white,round,biconvex,uncoatedtabletsdebossedwith‘F’ononesideand‘18’ontheotherside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inpost-menopausalwomenwithosteoporosis,AlendronicacidCeftisindicatedforthetreatmentofosteoporosisto

preventfractures,includingthoseofthehipandspine(vertebralcompressionfractures).

AlendronicacidCeftisindicatedforthetreatmentofosteoporosisinmentopreventfractures.

AlendronicacidCeftisindicatedforthetreatmentandpreventionofglucocorticoid-inducedosteoporosisinmenand

women.

Inpost-menopausalwomenwhoareatriskofdevelopingosteoporosisAlendronicacidCeftisindicatedforthe

preventionofosteoporosistoreducetheriskoffuturefracture.

4.2Posologyandmethodofadministration

Treatmentofosteoporosisinpostmenopausalwomen

Therecommendeddoseis10mgonceaday.

Treatmentofosteoporosisinmen

Therecommendeddoseis10mgonceaday.

Treatmentandpreventionofglucocorticoid-inducedosteoporosis

Forpost-menopausalwomennotreceivingharmonereplacementtherapy(HRT)withanoestrogen,therecommended

dosageis10mgonceaday.

Forotherpatients(i.e.men,pre-menopausalwomenandpost-menopausalwomenreceivingHRTwithanoestrogen),

therecommendeddosageis5mgonceaday.

Preventionofosteoporosisinpost-menopausalwomen:Therecommendeddosageis5mgonceaday.

Topermitadequateabsorptionofalendronicacid:

Alendronicacidmustbetakenatleast30minutesbeforethefirstfood,beverage,ormedicinalproductofthedaywith

plainwateronly.Otherbeverages(includingmineralwater),foodandsomemedicinalproductsarelikelytoreducethe

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Tofacilitatedeliverytothestomachandthusreducethepotentialforlocalandoesophagealirritation/adverse

experiences(seesection4.4):

Alendronicacidshouldonlybeswalloweduponarisingforthedaywithafullglassofwater(notlessthan200ml

or7fl.oz.).

Patientsshouldonlyswallow'AlendronicacidCeft'whole.Patientsshouldnotcrushorchewthetabletorallow

thetablettodissolveintheirmouthsbecauseofapotentialfororopharyngealulceration.

Patientsshouldnotliedownuntilaftertheirfirstfoodofthedaywhichshouldbeatleast30minutesaftertaking

thetablet.

Patientsshouldnotliedownforatleast30minutesaftertakingalendronicacid.

Alendronicacidshouldnotbetakenatbedtimeorbeforearisingfortheday.

AllpatientswithosteoporosisshouldreceivesupplementalcalciumandvitaminDifdietaryintakeisinadequate(see

section4.4).

Useintheelderly:Inclinicalstudiestherewasnoage-relateddifferenceintheefficacyorsafetyprofilesofalendronic

acid.Thereforenodosageadjustmentisnecessaryfortheelderly.

Useinrenalimpairment:Nodosageadjustmentisnecessaryforpatientswithmild-to-moderaterenalinsufficiency

(creatinineclearance35-60ml/min).Alendronicacidisnotrecommendedforpatientswithmoresevererenal

insufficiency(creatinineclearance<35ml/min).

Useinhepaticimpairment:Nodosageadjustmentisnecessary(see5.2'Pharmacokineticproperties',

biotransformation).

Paediatricpatients:Alendronatesodiumisnotrecommendedforuseinchildrenundertheageof18yearsdueto

insufficientdataonsafetyandefficacyinconditionsassociatedwithpaediatricosteoporosis(alsoseesection

5.1).

Clinicalexperiencewith'AlendronicAcidCeft'isavailableforaperiodoffiveyears:extensionstudiesareongoing.

Theeffectsoflonger-termtherapyareunknown.

Theoptimaldurationofbisphosphonatetreatmentforosteoporosishasnotbeenestablished.Theneedforcontinued

treatmentshouldbere-evaluatedperiodicallybasedonthebenefitsandpotentialrisksofalendronicacidonan

individualpatientbasis,particularlyafter5ormoreyearsofuse.

4.3Contraindications

Hypersensitivitytothealendronicacidortoanyoftheexcipients.

Abnormalitiesoftheoesophagusandotherfactorswhichdelayoesophagealemptyingsuchasstrictureor

achalasia.

Inabilitytostandorsituprightforatleast30minutes.

Hypocalcaemia(seealsosection4.4.)

4.4Specialwarningsandprecautionsforuse

Thisproductcontainsanoveldrugsubstance.Anyside-effectsoradversedrugreactionsassociatedwithitsuseshould

bereported.

Alendronicacidcancauselocalirritationoftheuppergastro-intestinalmucosa.Becausethereisapotentialfor

worseningoftheunderlyingdisease,cautionshouldbeusedwhenalendronicacidisgiventopatientswithactiveupper

gastro-intestinalproblems,suchasdysphagia,oesophagealdisease,gastritis,duodenitis,ulcers,orwitharecenthistory

(withinthepreviousyear)ofmajorgastro-intestinaldiseasesuchaspepticulcer,oractivegastro-intestinalbleeding,or

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InpatientswithknownBarrett’soesophagous,prescribersshouldconsiderthebenefitsandpotentialrisksofalendronic

acidonanindividualpatientbasis.

Oesophagealreactions(sometimessevereandrequiringhospitalisation),suchasoesophagitis,oesophagealulcersand

oesophagealerosions,rarelyfollowedbyoesophagealstricture,havebeenreportedinpatientsreceivingalendronic

acid.Physiciansshouldthereforebealerttoanysignsorsymptomssignallingapossibleoesophagealreactionand

patientsshouldbeinstructedtodiscontinuealendronicacidandseekmedicalattentioniftheydevelopsymptomsof

oesophagealirritationsuchasdysphagia,painonswallowingorretrosternalpain,neworworseningheartburn.

Theriskofsevereoesophagealadverseexperiencesappearstobegreaterinpatientswhofailtotakealendronicacid

properlyand/orwhocontinuetotakealendronicacidafterdevelopingsymptomssuggestiveofoesophagealirritation.It

isveryimportantthatthefulldosinginstructionsareprovidedto,andunderstoodbythepatient(seesection4.2).

Patientsshouldbeinformedthatfailuretofollowtheseinstructionsmayincreasetheirriskofoesophagealproblems.

Whilenoincreasedriskwasobservedinextensiveclinicaltrials,therehavebeenrare(post-marketing)reportsof

gastricandduodenalulcers,somesevereandwithcomplications.

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.

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

thesesymptomshaverarelybeensevereand/orincapacitating(seesection4.8).Thetimetoonsetofsymptomsvaried

fromonedaytoseveralmonthsafterstartingtreatment.Mostpatientshadreliefofsymptomsafterstopping.Asubset

hadrecurrenceofsymptomswhenrechallengedwiththesamedrugoranotherbisphosphonate.

AlendronicacidisnotrecommendedforpatientswithrenalimpairmentwhereGFRislessthan35ml/min,(seesection

4.2).

Causesofosteoporosisotherthanoestrogendeficiencyandageingshouldbeconsidered.

Hypocalcaemiamustbecorrectedbeforeinitiatingtherapywithalendronicacid(seesection4.3).Otherdisorders

affectingmineralmetabolism(suchasvitaminDdeficiencyandhypoparathyroidism)shouldalsobeeffectivelytreated.

Inpatientswiththeseconditions,serumcalciumandsymptomsofhypocalcaemiashouldbemonitoredduringtherapy

withalendronicacid.

Duetopositiveeffectsofalendronicacidinincreasingbonemineral,decreasesinserumcalciumandphosphatemay

occur.Theseareusuallysmallandasymptomatic.However,therehavebeenreportsofsymptomatichypocalcaemia,

whichoccasionallyhavebeensevereandoftenoccurredinpatientswithpredisposingconditions(e.g.

hypoparathyroidism,vitaminDdeficiencyandcalciummalabsorption).EnsuringadequatecalciumandvitaminD

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Atypicalfracturesofthefemur

Atypicalsubtrochantericanddiaphysealfemoralfractureshavebeenreportedwithbisphosphonatetherapy,primarily

inpatientsreceivinglong-termtreatmentforosteoporosis.Thesetransverseorshortobliquefracturescanoccur

anywherealongthefemurfromjustbelowthelessertrochantertojustabovethesupracondylarflare.Thesefractures

occurafterminimalornotraumaandsomepatientsexperiencethighorgroinpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fracturesareoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureshasalsobeenreported.Discontinuationofbisphosphonate

therapyinpatientssuspectedtohaveanatypicalfemurfractureshouldbeconsideredpendingevaluationofthepatient,

basedonanindividualbenefitriskassessment.

Duringbisphosphonatetreatmentpatientsshouldbeadvisedtoreportanythigh,hiporgroinpainandanypatient

presentingwithsuchsymptomsshouldbeevaluatedforanincompletefemurfracture.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Iftakenatthesametime,itislikelythatcalciumsupplements,antacids,andsomeoralmedicinalproductswillinterfere

withabsorptionofalendronicacid.Therefore,patientsmustwaitatleast30minutesaftertakingalendronicacidbefore

takinganyotheroralmedication.

Nootherdruginteractionsofclinicalsignificanceareanticipated.

Nootherinteractionswithmedicinalproductsofclinicalsignificanceareanticipated.Anumberofpatientsinthe

clinicaltrialsreceivedoestrogen(intravaginal,transdermal,ororal)whiletakingalendronate.Noadverseexperiences

attributabletotheirconcomitantusewereidentified.

SinceNSAIDuseisassociatedwithgastrointestinalirritation,cautionshouldbeusedduringconcomitantusewith

alendronate.

Althoughspecificinteractionstudieswerenotperformed,inclinicalstudiesalendronatewasusedconcomitantlywitha

widerangeofcommonlyprescribedmedicinalproductswithoutevidenceofclinicaladverseinteractions.

4.6Fertility,pregnancyandlactation

Useduringpregnancy

AlendronicacidCeftshouldnotbeusedduringpregnancy.Therearenoadequatedatafromtheuseofalendronatein

pregnantwomen.Animalstudiesdonotindicatedirectharmfuleffectswithrespecttopregnancy,embryonal/fetal

development,orpostnataldevelopment.Alendronategivenduringpregnancyinratscauseddystociarelatedto

hypocalcemia(see5.3'Preclinicalsafetydata').

Useduringlactation

Itisnotknownwhetheralendronicacidisexcretedintohumanbreastmilk.AlendronicacidCeftshouldnotbeusedby

breast-feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheabilitytodriveandusemachineshavebeenperformed.However,certainadversereactionsthathave

beenreportedwithalendronicacidmayaffectsomepatients'abilitytodriveoroperatemachinery.Individualresponses

toalendronicacidmayvary.(See4.8Undesirableeffects).

4.8Undesirableeffects

AlendronicAcidCeft'hasbeenstudiedinninemajorclinicalstudies(n=5,886).Inthelongestrunningtrialsinpost-

menopausalwomenuptofiveyearsexperiencehasbeencollected.Twoyearssafetydataareavailableinbothmen

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Thefollowingadverseexperienceshavealsobeenreportedduringclinicalstudiesand/orpost-marketinguse:

[Common(1/100,<1/10),Uncommon(1/1000,<1/100),Rare(1/10,000,<1/1000),Veryrare(<1/10,000

includingisolatedcases)]

Immunesystemdisorders:

Rare:hypersensitivityreactionsincludingurticariaandangioedema

Metabolismandnutritiondisorders:

Rare:symptomatichypocalcaemia,ofteninassociationwithpredisposingconditions.(seesection4.4)

Nervoussystemdisorders:

Common:headache

Eyedisorders:

Rare:uveitis,scleritis,episcleritis

Gastrointestinaldisorders:

Common:abdominalpain,dyspepsia,constipation,diarrhoea,flatulence,oesophagealulcer*,dysphagia*,abdominal

distension,acidregurgitation

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

Rare:oesophagealstricture*,oropharyngealulceration*,uppergastrointestinalPUBs(perforation,ulcers,bleeding)

(seesection4.4)

*Seesections4.2and4.4

Skinandsubcutaneoustissuedisorders:

Uncommon:rash,pruritus,erythema

Rare:rashwithphotosensitivity

Veryrareandisolatedcases:isolatedcasesofsevereskinreactionsincludingStevens-Johnsonsyndromeandtoxic

epidermalnecrolysis

Musculoskeletal,connectivetissueandbonedisorders:

Common:musculoskeletal(bone,muscleorjoint)pain

Rare:Osteonecrosisofthejawhasbeenreportedinpatientstreatedbybisphosphonates.Themajorityofthereports

refertocancerpatients,butsuchcaseshavealsobeenreportedinpatientstreatedforosteoporosis.Osteonecrosisofthe

jawisgenerallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis).Diagnosisofcancer,

chemotherapy,radiotherapy,corticosteroidsandpoororalhygienearealsodeemedasriskfactors;severe

musculoskeletal(bone,muscleorjoint)pain(seeSection4.4).

Generaldisordersandadministrationsiteconditions:

Rare:transientsymptomsasinanacute-phaseresponse(myalgia,malaiseandrarely,fever),typicallyinassociation

withinitiationoftreatment.

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyunknown):

Nervoussystemdisorders:dizziness,dysgeusia

Earandlabyrinthdisorders:vertigo

Skinandsubcutaneoustissuedisorders:alopecia

Musculoskeletal,connectivetissueandbonedisorders:jointswelling.

Generaldisordersandadministrationsiteconditions:asthenia,peripheraloedema

Laboratorytestfindings

Inclinicalstudies,asymptomatic,mildandtransientdecreasesinserumcalciumandphosphatewereobservedin

approximately18and10%,respectively,ofpatientstakingalendronicacid10mg/dayversusapproximately12and3%

ofthosetakingplacebo.However,theincidencesofdecreasesinserumcalciumto<8.0mg/dl(2.0mmol/l)andserum

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Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyrare):

Atypicalsubtrochantericanddiaphysealfemoralfractures(bisphosphonateclassadversereaction)

4.9Overdose

Significantlethalityaftersingleoraldoseswasseeninfemaleratsandmiceat552mg/kg(3,256mg/m 2

)and966

mg/kg(2,898mg/m 2

)(2,760and4,830times*therecommendeddoseforthetreatmentofosteoporosisinpost-

menopausalwomen),respectively.Inmales,thesevalueswereslightlyhigher,626and1,280mg/kg,respectively.

Therewasnolethalityindogsatoraldosesupto200mg/kg(4,000mg/m 2

)(1,000times*therecommendeddosefor

thetreatmentofosteoporosisinpost-menopausalwomen).

Nospecificinformationisavailableonthetreatmentofoverdosagewithalendronicacid.Hypocalcaemia,

hypophosphataemiaanduppergastro-intestinaladverseevents,suchasupsetstomach,heartburn,oesophagitis,

gastritis,orulcer,mayresultfromoraloverdosage.Milkorantacidsshouldbegiventobindalendronate.Owingtothe

riskofoesophagealirritation,vomitingshouldnotbeinducedandthepatientshouldremainfullyupright.

*Basedonapatientweightof50kg.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Drugsaffectingbonestructureandmineralisation,biphosphonate.

ATCCode:M05BA04

Alendronicacidisabisphosphonatethatinhibitsosteoclasticboneresorptionwithnodirecteffectonboneformation.

Theboneformedduringtreatmentwithalendronicacidisofnormalquality.

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.

Preventionofpost-menopausalosteoporosis

Theeffectsofalendronicacidtopreventbonelosswereexaminedintwostudiesofpost-menopausalwomenaged60

years.Inthelargerstudyof1,609women(6monthspost-menopausal)thosereceivingalendronicacid5mgdailyfor

twoyearshadBMDincreasesof3.5%,1.3%,3.0%and0.7%atthespine,femoralneck,trochanterandtotalbody,

respectively.Inthesmallerstudy(n=447),similarresultswereobservedinwomen(6to36monthspost-menopausal)

treatedwithalendronicacid5mgdailyforthreeyears.Incontrast,inbothstudies,womenreceivingplacebolostbone

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Thelongertermeffectsofalendronicacidinanosteoporosispreventionpopulationarenotknownbutclinicaltrial

extensionsofupto10yearsofcontinuoustreatmentarecurrentlyinprogress.

Concomitantusewithoestrogen/hormonereplacementtherapy(HRT)

TheeffectsonBMDoftreatmentwithalendronicacid10mgonce-dailyandconjugatedoestrogen(0.625mg/day)

eitheraloneorincombinationwereassessedinatwo-yearstudyofhysterectomised,post-menopausal,osteoporotic

women.Attwoyears,theincreasesinlumbarspineBMDfrombaselineweresignificantlygreaterwiththe

combination(8.3%)thanwitheitheroestrogenoralendronicacidalone(both6.0%).

TheeffectsonBMDwhenalendronicacidwasaddedtostabledoses(foratleastoneyear)ofHRT(oestrogen±

progestin)wereassessedinaone-yearstudyinpost-menopausal,osteoporoticwomen.Theadditionofalendronicacid

10mgonce-dailytoHRTproduced,atoneyear,significantlygreaterincreasesinlumbarspineBMD(3.7%)vs.HRT

alone(1.1%).

Inthesestudies,significantincreasesorfavourabletrendsinBMDforcombinedtherapycomparedwithHRTalone

wereseenatthetotalhip,femoralneckandtrochanter.NosignificanteffectwasseenfortotalbodyBMD.

Treatmentofosteoporosisinmen

Theefficacyofalendronicacid10mgoncedailyinmen(ages31to87;mean,63)withosteoporosiswasdemonstrated

inatwo-yearstudy.Attwoyears,themeanincreasesrelativetoplaceboinBMDinmenreceivingalendronicacid10

mg/daywere:lumbarspine,5.3%;femoralneck,2.6%;trochanter,3.1%;andtotalbody,1.6%.alendronicacidwas

effectiveregardlessofage,race,gonadalfunction,baselinerateofboneturnover,orbaselineBMD.Consistentwith

muchlargerstudiesinpost-menopausalwomen,inthesemen,alendronicacid10mg/dayreducedtheincidenceofnew

vertebralfracture(assessedbyquantitativeradiography)relativetoplacebo(0.8%vs.7.1%)and,correspondingly,also

reducedheightloss(-0.6vs.-2.4mm).

Glucocorticoid-inducedosteoporosis

Theefficacyofalendronicacid5and10mgonce-dailyinmenandwomenreceivingatleast7.5mg/dayofprednisone

(orequivalent)wasdemonstratedintwo,one-yearstudies.Atoneyear,themeanincreasesrelativetoplaceboinBMD

inpatientsreceivingalendronicacid5mg/dayfromthecombinedstudieswere:lumbarspine,2.4%;femoralneck,

2.2%;andtrochanter,1.6%.TotalbodyBMDwasmaintainedwiththisdoseofalendronicacid.TheincreasesinBMD

withalendronicacid10mg/dayweresimilartothosewithalendronicacid5mg/dayinallpatientsexceptforthose

post-menopausalwomennotreceivingoestrogentherapy.Inthesewomen,theincreases(relativetoplacebo)with

alendronicacid10mg/dayweregreaterthanthosewithalendronicacid5mg/dayatthelumbarspine(4.1%vs.1.6%)

andtrochanter(2.8%vs.1.7%),butnotatothersites.alendronicacidwaseffectiveregardlessofdoseordurationof

glucocorticoiduse.

Themajorityofpatientsfromthesestudieswhoremainedonatleast7.5mg/dayofprednisoneorequivalentcontinued

intoaone-yearextension.Aftertwoyearsoftreatment,spineBMDincreasedby3.7%and5.0%relativetoplacebo

withalendronicacid5and10mg/dayrespectively.SignificantincreasesinBMD(relativetoplacebo)werealso

observedatthefemoralneck,trochanter,andtotalbody.Whenthedatafromthethreedosagegroups(5or10mgfor

twoyearsor2.5mgforoneyearfollowedby10mgforoneyear)waspooled,therewasasignificantreductioninthe

incidenceofpatientswithanewvertebralfractureattwoyears(alendronicacid,0.7%vsplacebo,6.8%).

Paediatricpatients:

Alendronatesodiumhasbeenstudiedinasmallnumberofpatientswithosteogenesisimperfectaundertheageof18

years.Resultsareinsufficienttosupporttheuseofalendronatesodiuminpaediatricpatientswithosteogenesis

imperfecta.

5.2Pharmacokineticproperties

Absorption

Relativetoanintravenous(IV)referencedose,theoralbioavailabilityofalendronateinwomenwas0.7%fordoses

rangingfrom5to40mgwhenadministeredafteranovernightfastandtwohoursbeforeastandardisedbreakfast.Oral

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Bioavailabilitywasdecreasedsimilarly(byapproximately40%)whetheralendronatewasadministeredonehouror

halfanhourbeforeastandardisedbreakfast.Inosteoporosisstudies,alendronicacidwaseffectivewhenadministered

atleast30minutesbeforethefirstfoodorbeverageoftheday.

Bioavailabilitywasnegligiblewhetheralendronatewasadministeredwith,oruptotwohoursafter,astandardised

breakfast.Concomitantadministrationofalendronatewithcoffeeororangejuicereducedbioavailabilityby

approximately60%.

Inhealthysubjects,oralprednisone(20mgthreetimesdailyforfivedays)didnotproduceaclinicallymeaningful

changeintheoralbioavailabilityofalendronate(ameanincreaserangingfrom20to44%).

Distribution

Studiesinratsshowthatalendronatetransientlydistributestosofttissuesfollowing1mg/kgIVadministrationbutis

thenrapidlyredistributedtoboneorexcretedintheurine.Themeansteady-statevolumeofdistribution,exclusiveof

bone,isatleast28litresinhumans.Concentrationsofdruginplasmafollowingtherapeuticoraldosesaretoolowfor

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

Biotransformation

Thereisnoevidencethatalendronateismetabolisedinanimalsorhumans.

Elimination

FollowingasingleIVdoseof[ 14

C]alendronate,approximately50%oftheradioactivitywasexcretedintheurine

within72hoursandlittleornoradioactivitywasrecoveredinthefaeces.Followingasingle10mgIVdose,therenal

clearanceofalendronatewas71ml/min,andsystemicclearancedidnotexceed200ml/min.Plasmaconcentrationsfell

bymorethan95%within6hoursfollowingIVadministration.Theterminalhalf-lifeinhumansisestimatedtoexceed

tenyears,reflectingreleaseofalendronatefromtheskeleton.Alendronateisnotexcretedthroughtheacidicorbasic

transportsystemsofthekidneyinrats,andthusitisnotanticipatedtointerferewiththeexcretionofotherdrugsby

thosesystemsinhumans.

Characteristicsinpatients

Preclinicalstudiesshowthatthedrugthatisnotdepositedinboneisrapidlyexcretedintheurine.Noevidenceof

saturationofboneuptakewasfoundafterchronicdosingwithcumulativeIVdosesupto35mg/kginanimals.

Althoughnoclinicalinformationisavailable,itislikelythat,asinanimals,eliminationofalendronateviathekidney

willbereducedinpatientswithimpairedrenalfunction.Therefore,somewhatgreateraccumulationofalendronatein

bonemightbeexpectedinpatientswithimpairedrenalfunction(see4.2'Posologyandmethodofadministration').

5.3Preclinicalsafetydata

Noadditionalrelevantinformation.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Cellulose,Microcrystalline

MaizeStarch

SodiumStarchGlycolate(TypeA)

Povidone(K-30)

Magnesiumstearate

6.2Incompatibilities

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6.3Shelflife

2years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

ThetabletsaresuppliedinPVC/Aclar–AluminiumblisterpackandHDPEcontainerpack.

Packsize:

PVC/Aclar–Aluminiumblisterpack:10,14,20,28,30,50,56,60,84,90,98,100,112,140and250tablets

HDPEcontainerpack:30,50,100,250and1000tablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposal

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

CeftLimited

65DelamereRoad,Hayes

MiddlesexUB40NN

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA1524/2/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:7 th

October2011

Irish Medicines Board

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Date Printed 10/10/2011 CRN 2058435 page number: 9