ALENDROMAX 10MG TABLETS

Main information

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

Documents

Localization

  • Available in:
  • ALENDROMAX 10MG TABLETS
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1130/020/001
  • Authorization date:
  • 28-11-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Alendromax10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontains10mgalendronicacid(assodiumalendronatetrihydrate).

Excipient:

Eachtabletcontains103.95mglactosemonohydrate

Forafulllistofexcipientsseesection6.1.

3PHARMACEUTICALFORM

Tablet

Whitetooff-white,capsule-shapedtablet,embossed"AN10"ononesideand"Arrowlogo"ontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpost-menopausalosteoporosis.

Alendronatereducestheriskofvertebralandhipfractures.

Treatmentofosteoporosisinmen.

Alendronatereducestheriskofvertebralfractures.

Treatmentandprophylaxisofglucocorticoid-inducedosteoporosisinpost-menopausal

womenwhoarenotreceivinghormonereplacementtherapy(HRT)withanoestrogen.

See5.1Pharmacodynamicproperties.

4.2Posologyandmethodofadministration

Post-menopausalosteoporosis:

Therecommendeddosageis10mgoncedaily.

Osteoporosisinmen:

Therecommendeddosageis10mgoncedaily.

Glucocorticoid-inducedosteoporosis:

Forpost-menopausalwomenwhoarenotreceivingoestrogentreatmenttherecommendeddoseisone10mgtablet

daily.Forotherpatients,preparationscontaining5mgalendronateshouldbeused.

Theoptimaldurationofbisphosphonatetreatmentforosteoporosishasnotbeenestablished.Theneedforcontinued

treatmentshouldbere-evaluatedperiodicallybasedonthebenefitsandpotentialrisksofAlendromaxonanindividual

patientbasis,particularlyafter5ormoreyearsofuse.

Topermitadequateabsorptionofalendronate:

Alendromax10mgtabletsmustbetakenatleast30minutesbeforethefirstfood,beverage,ormedicinalproductofthe

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Otherbeverages(includingmineralwater),foodandsomemedicinalproductsarelikelytoreducetheabsorptionof

alendronate(see4.5‘Interactionwithothermedicinalproductsandotherformsofinteraction’).

Tofacilitatedeliverytothestomachandthusreducethepotentialforlocalandoesophagealirritation/adverse

experiences(see4.4‘Specialwarningsandprecautionsforuse’):

Alendromax10mgtabletsshouldonlybeswalloweduponarisingforthedaywithafullglassofwater(not

lessthan200mlor7fl.oz.).

PatientsshouldonlyswallowAlendromax10mgtabletswhole.Patientsshouldnotcrushorchewthetabletor

allowthetablettodissolveintheirmouthsbecauseofapotentialfororopharyngealulceration.

Patientsshouldnotliedownuntilaftertheirfirstfoodofthedaywhichshouldbeatleast30minutesafter

takingthetablet.

Patientsshouldnotliedownforatleast30minutesaftertakingAlendromax10mgtablets.

Alendromax10mgtabletsshouldnotbetakenatbedtimeorbeforearisingfortheday.

PatientsshouldreceivesupplementalcalciumandvitaminDifdietaryintakeisinadequate(see4.4‘Specialwarnings

andprecautionsforuse’).

Useintheelderly:Inclinicalstudiestherewasnoage-relateddifferenceintheefficacyorsafetyprofilesof

alendronate.Thereforenodosageadjustmentisnecessaryfortheelderly.

Useinrenalimpairment:NodosageadjustmentisnecessaryforpatientswithGFRgreaterthan35ml/min.

AlendronateisnotrecommendedforpatientswithrenalimpairmentwhereGFRislessthan35ml/min,duetolackof

experience.

Useinchildren(under18years):Alendronatehasbeenstudiedinasmallnumberofpatientswithosteogenesis

imperfectaunder18yearsofage.Resultsareinsufficienttosupportitsuseinchildren.Alendromax10mgtabletshave

notbeeninvestigatedinthetreatmentofglucocorticoidsinducedosteoporosis.

4.3Contraindications

Abnormalitiesoftheoesophagusandotherfactorswhichdelayoesophagealemptyingsuchasstrictureor

achalasia.

Inabilitytostandorsituprightforatleast30minutes.

Hypersensitivitytoalendronateortoanyoftheexcipients.

Hypocalcaemia.

Seealso4.4Specialwarningsandprecautionsforuse.

4.4Specialwarningsandprecautionsforuse

Alendronatecancauselocalirritationoftheuppergastro-intestinalmucosa.Becausethereisapotentialforworsening

oftheunderlyingdisease,cautionshouldbeusedwhenalendronateisgiventopatientswithactiveuppergastro-

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

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

surgeryoftheuppergastrointestinaltractotherthanpyloroplasty(see4.3‘Contraindications’).

InpatientswithknownBarrett'soesophagus,prescribersshouldconsiderthebenefitsandpotentialrisksofalendronate

onanindividualpatientbasis.

Oesophagealreactions(sometimessevereandrequiringhospitalisation),suchasoesophagitis,oesophagealulcersand

oesophagealerosions,rarelyfollowedbyoesophagealstricture,havebeenreportedinpatientsreceivingalendronate.

Physiciansshouldthereforebealerttoanysignsorsymptomssignallingapossibleoesophagealreactionandpatients

shouldbeinstructedtodiscontinuealendronateandseekmedicalattentioniftheydevelopsymptomsofoesophageal

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Theriskofsevereoesophagealadverseexperiencesappearstobegreaterinpatientswhofailtotakealendronate

properlyand/orwhocontinuetotakealendronateafterdevelopingsymptomssuggestiveofoesophagealirritation.Itis

veryimportantthatthefulldosinginstructionsareprovidedto,andunderstoodbythepatient(see4.2‘Posologyand

methodofadministration’).Patientsshouldbeinformedthatfailuretofollowtheseinstructionsmayincreasetheirrisk

ofoesophagealproblems.

Whilenoincreasedriskwasobservedinextensiveclinicaltrials,therehavebeenrare(postmarketing)reportsofgastric

andduodenalulcers,somesevereandwithcomplications.

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimensincludingprimarilyintravenouslyadministered

bisphosphonates.Manyofthesepatientswerealsoreceivingchemotherapyandcorticosteroids.Osteonecrosisofthe

jawhasalsobeenreportedinpatientswithosteoporosisreceivingoralbisphosphonates.

Adentalexaminationwithappropriatepreventivedentistryshouldbeconsideredpriortotreatmentwith

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

poororalhygiene,periodontaldisease,smoking).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbisphosphonatetherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbisphosphonatetreatment

reducestheriskofosteonecrosisofthejaw.Clinicaljudgementofthetreatingphysicianshouldguidethemanagement

planofeachpatientbasedonindividualbenefit/riskassessment.

Atypicalfracturesofthefemur

Atypicalsubtrochantericanddiaphysealfemoralfractureshavebeenreportedwithbisphosphonatetherapy,primarily

inpatientsreceivinglong-termtreatmentforosteoporosis.Thesetransverseorshortoblique,fracturescanoccur

anywherealongthefemurfromjustbelowthelessertrochantertojustabovethesupracondylarflare.Thesefractures

occurafterminimalornotraumaandsomepatientsexperiencethighorgroinpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fracturesareoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureshasalsobeenreported.Discontinuationofbisphosphonate

therapyinpatientssuspectedtohaveanatypicalfemurfractureshouldbeconsideredpendingevaluationofthepatient,

basedonanindividualbenefitriskassessment.Duringbisphosphonatetreatmentpatientsshouldbeadvisedtoreport

anythigh,hiporgroinpainandanypatientpresentingwithsuchsymptomsshouldbeevaluatedforanincomplete

femurfracture.

Bone,joint,and/ormusclepainhasbeenreportedinpatientstakingbisphosphonates.Inpostmarketingexperience,

thesesymptomshaverarelybeensevereand/orincapacitating(see‘4.8Undesirableeffects’).

Thetimetoonsetofsymptomsvariedfromonedaytoseveralmonthsafterstartingtreatment.Mostpatientshadrelief

ofsymptomsafterstopping.Asubsethadrecurrenceofsymptomswhenrechallengedwiththesamedrugoranother

bisphosphonate.

PatientsshouldbeinstructedthatiftheymissadoseofAlendromax10mgtablets,theyshouldtakeonetabletonthe

morningaftertheyremember.Theyshouldnottaketwotabletsonthesamedaybutshouldreturntotakingonetablet

onceaday,asoriginallyscheduled.

AlendronateisnotrecommendedforpatientswithrenalimpairmentwhereGFRislessthan35ml/min,(see4.2

‘Posologyandmethodofadministration’).

Causesofosteoporosisotherthanoestrogendeficiencyandageingshouldbeconsidered.

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Otherdisordersaffectingmineralmetabolism(suchasvitaminDdeficiencyandhypoparathyroidism)shouldalsobe

effectivelytreated.Inpatientswiththeseconditions,serumcalciumandsymptomsofhypocalcemiashouldbe

monitoredduringtherapywithAlendromax10mgtablets.

Duetothepositiveeffectsofalendronateinincreasingbonemineral,decreasesinserumcalciumandphosphatemay

occurespeciallyinpatientstakingglucocorticoidsinwhomcalciumabsorptionmaybedecreased.Theseareusually

smallandasymptomatic.However,therehavebeenrarereportsofsymptomatichypocalcemia,whichhave

occasionallybeensevereandoftenoccurredinpatientswithpredisposingconditions(e.g.hypoparathyroidism,vitamin

Ddeficiencyandcalciummalabsorption).EnsuringadequatecalciumandvitaminDintakeisparticularlyimportantin

patientsreceivingglucocorticoids.

Excipients

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicinalproduct.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Iftakenatthesametime,itislikelythatfoodandbeverages(includingmineralwater),calciumsupplements,antacids,

andsomeoralmedicinalproductswillinterferewithabsorptionofalendronate.Therefore,patientsmustwaitatleast30

minutesaftertakingalendronatebeforetakinganyotheroralmedicinalproduct(see4.2‘Posologyandmethodof

administration’and5.2‘Pharmacokineticproperties’).

Nootherinteractionswithmedicinalproductsofclinicalsignificanceareanticipated.Anumberofpatientsinthe

clinicaltrialsreceivedoestrogen(intravaginal,transdermal,ororal)whiletakingalendronate.Noadverseexperiences

attributabletotheirconcomitantusewereidentified.

SinceNSAIDuseisassociatedwithgastrointestinalirritation,cautionshouldbeusedduringconcomitantusewith

alendronate.Althoughspecificinteractionstudieswerenotperformed,inclinicalstudiesalendronatewasused

concomitantlywithawiderangeofcommonlyprescribedmedicinalproductswithoutevidenceofclinicaladverse

interactions.

4.6Fertility,pregnancyandlactation

Useduringpregnancy

Alendronateshouldnotbeusedduringpregnancy.Therearenoadequatedatafromtheuseofalendronateinpregnant

women.Animalstudiesdonotindicatedirectharmfuleffectswithrespecttopregnancy,embryonal/fetaldevelopment,

orpostnataldevelopment.Alendronategivenduringpregnancyinratscauseddystociarelatedtohypocalcemia(see5.3

‘Preclinicalsafetydata’).

Useduringlactation

Itisnotknownwhetheralendronateisexcretedintohumanbreastmilk.Alendronateshouldnotbeusedbybreast-

feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheeffectsontheabilitytodriveandusemachineshavebeenperformed.However,certainadverse

reactionsthathavebeenreportedwithAlendromaxmayaffectsomepatients'abilitytodriveoroperatemachinery.

IndividualresponsestoAlendromaxmayvary.(See4.8Undesirableeffects).

4.8Undesirableeffects

Inaone-yearstudyinpost-menopausalwomenwithosteoporosistheoverallsafetyprofilesofAlendronatesodium

OnceWeekly70mg(n=519)andalendronate10mg/day(n=370)weresimilar.

Intwothree-yearstudiesofvirtuallyidenticaldesign,inpost-menopausalwomen(alendronate10mg:n=196,placebo:

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Adverseexperiencesreportedbytheinvestigatorsaspossibly,probablyordefinitelydrug-relatedarepresentedbelow

iftheyoccurredin1%ineithertreatmentgroupintheone-yearstudy,orin1%ofpatientstreatedwithalendronate

10mg/dayandatagreaterincidencethaninpatientsgivenplacebointhethree-yearstudies:

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

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Veryrareandisolatedcases:isolatedcasesofsevereskinreactionsincludingStevens-Johnsonsyndromeandtoxic

epidermalnecrolysis

Musculoskeletal,connectivetissueandbonedisorders:

Common:musculoskeletal(bone,muscleorjoint)pain

Rare:Osteonecrosisofthejawhasbeenreportedinpatientstreatedbybisphosphonates.Themajorityofthereports

refertocancerpatients,butsuchcaseshavealsobeenreportedinpatientstreatedforosteoporosis.Osteonecrosisofthe

jawisgenerallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis).Diagnosisofcancer,

chemotherapy,radiotherapy,corticosteroids,poororalhygieneandsmokingarealsodeemedasriskfactors;severe

musculoskeletal(bone,muscleorjoint)pain(see4.4‘Specialwarningsandprecautionsforuse’).

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyrare):Atypical

subtrochantericanddiaphysealfemoralfractures(bisphosphonateclassadversereaction)

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,ofpatientstakingalendronate10mg/dayversusapproximately12and3%of

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

phosphateto2.0mg/dl(0.65mmol/l)weresimilarinbothtreatmentgroups.

4.9Overdose

Hypocalcaemia,hypophosphataemiaanduppergastro-intestinaladverseevents,suchasupsetstomach,heartburn,

oesophagitis,gastritis,orulcer,mayresultfromoraloverdosage.

Nospecificinformationisavailableonthetreatmentofoverdosagewithalendronate.Milkorantacidsshouldbegiven

tobindalendronate.Owingtotheriskofoesophagealirritation,vomitingshouldnotbeinducedandthepatientshould

remainfullyupright.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:Drugsfortreatmentofbonediseases,bisphosphonates.

ATCcode:M05BA04

TheactivesubstanceinAlendromax10mgtablets,sodiumalendronatetrihydrate,isabisphosphonatethatinhibits

osteoclasticboneresorptionwithoutanydirecteffectonboneformation.Preclinicalstudieshavedemonstrateda

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Osteoclasticactivityisinhibited,butformationandbindingoftheosteoclastsisnotaffected.Boneformedduring

treatmentwithalendronateisofnormalquality.

Treatmentofpost-menopausalosteoporosis

Osteoporosisisdefinedasbonemineraldensity(BMD)ofthespineorhip2.5standarddeviationsbelowthe

meanvalueofanormalyoungpopulationorasapreviousfragilityfracture,irrespectiveofbonemineral

density.

TheeffectsofalendronateonBMDandfractureincidenceinpost-menopausalwomenwerestudiedintwoinitial

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

Intheinitialefficacystudies,theincreasesinBMDwithalendronate10mgdailyrelativetoplaceboafterthreeyears

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

significantly.Inthepatientstreatedwithalendronate,theproportionofpatientswhosufferedoneormorevertebral

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

theBMDinthespineandtrochantercontinuedtoincrease.Inaddition,BMDatthefemoralneckandtotalbodywas

maintained.

FITconsistedoftwoplacebo-controlledstudies:athree-yearstudyof2,027patientswhohadatleastonebaseline

vertebral(compression)fractureandafour-yearstudyof4,432patientswithlowbonemassbutwithoutabaseline

vertebralfracture,37%ofwhomhadosteoporosisasdefinedbyabaselinefemoralneckBMDatleast2.5standard

deviationsbelowthemeanforyoung,adultwomen.InallFITpatientswithosteoporosisfrombothstudies,

Alendronatetabletsreducedtheincidenceof: 1vertebralfractureby48%,multiplevertebralfracturesby87%, 1

painfulvertebralfractureby45%,anypainfulfractureby31%andhipfractureby54%.

OveralltheseresultsdemonstratetheconsistenteffectofAlendronatetabletstoreducetheincidenceoffractures,

includingthoseofthespineandhip,whicharethesitesofosteoporoticfractureassociatedwiththegreatestmorbidity.

Preventionofpost-menopausalosteoporosis

TheeffectsofAlendronatetabletstopreventbonelosswereexaminedintwostudiesofpost-menopausalwomenaged

60years.Inthelargerstudyof1,609women(6monthspost-menopausal)thosereceivingAlendronatetablets5mg

dailyfortwoyearshadBMDincreasesof3.5%,1.3%,3.0%and0.7%atthespinefemoralneck,trochanterandtotal

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

menopausal)treatedwithAlendronatetablets5mgdailyforthreeyears.Incontrast,inbothstudies,womenreceiving

placebolostbonemassatarateofapproximately1%peryear.ThelongertermeffectsofAlendronatetabletsinan

osteoporosispreventionpopulationarenotknownbutclinicaltrialextensionsofupto10yearsofcontinuoustreatment

arecurrentlyinprogress.

Concomitantusewithoestrogen/hormonereplacementtherapy(HRT)

TheeffectsonBMDoftreatmentwithAlendronatetablets10mgonce-dailyandconjugatedoestrogen(0.625mg/day)

eitheraloneorincombinationwereassessedintwo-yearstudyofhysterectomised,post-menopausal,osteoporotic

women.Attwoyears,theincreasesinlumbarspineBMDfrombaselineweresignificantlygreaterwiththe

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

TheeffectsonBMDwhenAlendronatetabletswasaddedtostabledoses(foratleastoneyear)ofHRT(oestrogen

±progestin)wereassessedinaone-yearstudyinpost-menopausal,osteoporoticwomen.TheadditionofAlendronate

tablets10mgonce-dailytoHRTproduced,atoneyear,significantlygreaterincreasesinlumbarspineBMD(3.7%)

vs.HRTalone(1.1%).

Inthesestudies,significantincreasesorfavourabletrendsinBMDforcombinedtherapycomparedwithHRTalone

wereseenatthetotalhip,femoralneckandtrochanter.NosignificanteffectwasseenfortotalbodyBMD.

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TheefficacyofAlendronatetablets10mgoncedailyinmen(ages31to87;mean63)withosteoporosiswas

demonstratedinatwo-yearstudy.Attwoyears,themeanincreasesrelativetoplaceboinBMDinmenreceiving

Alendronatetablets10mg/daywere;lumbarspine,5.3%;femoralneck,2.6%;trochanter,3.1%;andtotalbody,1.6%.

Alendronatetabletswaseffectiveregardlessofage,race,gonadalfunction,baselinerateofboneturnover,orbaseline

BMD.Consistentwithmuchlargerstudiesinpost-menopausalwomen,inthese127men,Alendronatetablets

10mg/dayreducedtheincidenceofnewvertebalfracture(assessedbyquantitiveradiography)relativetoplacebo(0.8%

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

Glucocorticoid-inducedosteoporosis

TheefficacyofAlendronatetablets5and10mgonce-dailyinmenandwomenreceivingatleast7.5mg/dayof

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

and5.0%(relativetoplacebo)withAlendronatetablets5and10mg/dayrespectively.SignificantincreasesinBMD

werealsoobservedatthefemoralneck,trochanter,andtotalbody.Inpost-menopausalwomennotreceiving

oestrogen,greaterincreasesinlumbarspineandtrochanterBMDwereseeninthosereceiving10mgAlendronate

tabletsthanthosereceiving5mg.Alendronatetabletswaseffectiveregardlessofdoseordurationofglucocorticoid

use.Datapooledfromthreegroups(5or10mgfortwoyearsor2.5mgforoneyearfollowedby10mgforoneyear)

showedasignificantreductionintheincidenceofpatientswithanewvertebralfractureattwoyears(Alendronate

tablets0.7%vs.placebo6.8).

5.2Pharmacokineticproperties

Absorption

Comparedwithanintravenousreferencedose,themeanoralbioavailabilityofalendronateinwomenwas0.64%for

dosesrangingfrom5to70mggivenafteranovernightfastandtwohoursbeforeastandardisedbreakfast.Theoral

bioavailabilityinmen(0.6%)wassimilartothatofwomen.Bioavailabilitydecreasedtoanestimated0.46%and

0.39%whenalendronatewasgivenanhourorhalfanhourbeforeastandardisedbreakfast.

Inosteoporosisstudiesalendronatewaseffectivewhenitwasgivenatleast30minutesbeforethefirstmealordrinkof

theday.Bioavailabilitywasnegligibleirrespectiveofwhetheralendronatewasgiventogetherwithoruptotwohours

afterastandardisedbreakfast.Concomitantadministrationofalendronatewithcoffeeororangejuicereduced

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

resultinanyclinicallymeaningfulchangeintheoralbioavailabilityofalendronate(ameanincreaserangingfrom20%

to44%).

Distribution

Studiesinratsshowthatalendronateisinitiallydistributedtosofttissuesafterintravenousadministrationof1mg/kg,

butisthenrapidlyredistributedtotheskeletonorexcretedintheurine.Themeansteady-statevolumeofdistribution,

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

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Characteristicsinpatients

Preclinicalstudiesshowthatthedrugthatisnotdepositedinboneisrapidlyexcretedintheurine.Noevidenceof

saturationofboneuptakewasfoundafterchronicdosingwithcumulativeintravenousdosesupto35mg/kginanimals.

Althoughnoclinicalinformationisavailable,itislikelythat,asinanimals,eliminationofalendronateviathekidney

willbereducedinpatientswithimpairedrenalfunction.Therefore,somewhatgreateraccumulationofalendronatein

bonemightbeexpectedinpatientswithimpairedrenalfunction(see4.2Posologyandmethodofadministration).

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.Storeintheoriginalpackage.

6.5Natureandcontentsofcontainer

Thetabletsaresuppliedintriplexblister(PVC/PE/PVDC/Aluminium)packaging.

14,28,56,98,112and50x1(unitdose).

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

ArrowGenericsLimited

Unit2

EastmanWay

Stevenage

HertfordshireSG14SZ

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8MARKETINGAUTHORISATIONNUMBER

PA1130/20/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:28November2008

Dateoflastrenewal:3December2009

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 22/03/2012 CRN 2109918 page number: 10