FOSAMAX

Main information

  • Trade name:
  • FOSAMAX Tablets 10 mg Milligram
  • Dosage:
  • 10 mg Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FOSAMAX Tablets 10 mg Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0035/083/001
  • Authorization date:
  • 08-01-1996
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Fosamax10mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletof‘Fosamax’10mgcontains13.05mgofalendronatesodium,whichisthemolarequivalentto10mgof

alendronicacid.

Forexcipients,see6.1.

3PHARMACEUTICALFORM

Tablet.

‘Fosamax’10mgissuppliedasovalwhitetablets,marked‘936’ononesideandplainontheother.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Inpost-menopausalwomenwithosteoporosis,‘Fosamax’isindicatedforthetreatmentofosteoporosistoprevent

fractures,includingthoseofthehipandspine(vertebralcompressionfractures).

‘Fosamax’isindicatedforthetreatmentofosteoporosisinmentopreventfractures.

‘Fosamax’isindicatedforthetreatmentandpreventionofglucocorticoid-inducedosteoporosisinmenandwomen.

Inpost-menopausalwomenwhoareatriskofdevelopingosteoporosis‘Fosamax’isindicatedforthepreventionof

osteoporosistoreducetheriskoffuturefracture.

4.2Posologyandmethodofadministration

Treatmentofosteoporosisinpost-menopausalwomen:Therecommendeddosageis10mgonceaday.

Treatmentofosteoporosisinmen:Therecommendeddosageis10mgonceaday.

Treatmentandpreventionofglucocorticoid-inducedosteoporosis:Forpost-menopausalwomennotreceiving

hormonereplacementtherapy(HRT)withanoestrogen,therecommendeddosageis10mgonceaday.

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

therecommendeddosageis5mgonceaday.

Preventionofosteoporosisinpost-menopausalwomen:Therecommendeddosageis5mgonceaday.

Topermitadequateabsorptionof‘Fosamax’:‘Fosamax’mustbetakenatleast30minutesbeforethefirstfood,

beverage,ormedicationofthedaywithplainwateronly.Otherbeverages(includingmineralwater),foodand

somemedicationsarelikelytoreducetheabsorptionof‘Fosamax’(see4.5‘Interactionwithothermedicaments

andotherformsofinteraction’).

Tofacilitatedeliverytothestomachandthusreducethepotentialforlocalandoesophagealirritation/adverse

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‘Fosamax’shouldonlybeswalloweduponrisingforthedaywithafullglassofwater(notlessthan200mlor

7fl.oz.).

Patientsshouldonlyswallow'Fosamax'whole.Patientsshouldnotcrushorchewthetabletorallowthetablet

todissolveintheirmouthsbecauseofapotentialfororopharyngealulceration.

Patientsshouldnotliedownforatleast30minutesaftertaking‘Fosamax’.

Patientsshouldnotliedownuntilaftertheirfirstfoodoftheday,whichshouldbeatleast30minutesafter

takingthetablet.

‘Fosamax’shouldnotbetakenatbedtimeorbeforerisingfortheday.

AllpatientswithosteoporosisshouldreceivesupplementalcalciumandvitaminDifdietaryintakeisinadequate(see

4.4‘Specialwarningsandprecautionforuse’).

Useintheelderly:Inclinicalstudies,therewasnoage-relateddifferenceintheefficacyorsafetyprofilesof

‘Fosamax’.Therefore,nodosageadjustmentisnecessaryfortheelderly.

Useinrenalimpairment:Nodosageadjustmentisnecessaryforpatientswithmild-to-moderaterenalinsufficiency

(creatinineclearance35-60ml/min).‘Fosamax’isnotrecommendedforpatientswithmoresevererenal

insufficiency(creatinineclearance<35ml/min).

Useinchildren(under18years):Aldronatehasbeenstudiedinasmallnumberofpatientswithosteogenesis

imperfectaunder18yearsofage.Resultsareinsufficienttosupportitsuseinchildren.

Useinhepaticimpairment:Nodosageadjustmentisnecessary(see5.2‘Pharmacokineticproperties’,

biotransformation).

Clinicalexperiencewith‘Fosamax’isavailableforaperiodoffiveyears:extensionstudiesareongoing.Theeffectsof

longer-termtherapyareunknown.

4.3Contraindications

Abnormalitiesoftheoesophagusandotherfactorswhichdelayoesophagealemptying,suchasstrictureor

achalasia.

Inabilitytostandorsituprightforatleast30minutes.

Hypersensitivitytoanycomponentofthisproduct.

Hypocalcaemia(see4.4‘Specialwarningsandprecautionsforuse’)

4.4Specialwarningsandprecautionsforuse

Thisproductcontainsanoveldrugsubstance.Anyside-effectsoradversedrugreactionsassociatedwithitsuseshould

bereported.

‘Fosamax’cancauselocalirritationoftheuppergastro-intestinalmucosa.Becausethereisapotentialforworsening

oftheunderlyingdisease,cautionshouldbeusedwhen‘Fosamax’isgiventopatientswithactiveuppergastro-

intestinalproblems,suchasdysphagia,oesophagealdisease,gastritis,duodenitis,orulcersorwitharecenthistory

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

surgeryoftheuppergastro-intestinaltractotherthanpyloroplasty(see4.3Contraindications’).Inpatientswithknown

Barrett'soesophagus,prescribersshouldconsiderthebenefitsandpotentialrisksofalendronateonanindividualpatient

basis.

Oesophagealreactions(sometimessevereandrequiringhospitalisation),suchasoesophagitis,oesophagealulcersand

oesophagealerosions,rarelyfollowedbyoesophagealstrictureorperforation,havebeenreportedinpatientsreceiving

‘Fosamax’.Physiciansshouldthereforebealerttoanysignsorsymptomssignallingapossibleoesophagealreaction,

andpatientsshouldbeinstructedtodiscontinue‘Fosamax’andseekmedicalattentioniftheydevelopsymptomsof

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Theriskofsevereoesophagealadverseexperienceappearstobegreaterinpatientswhofailtotake‘Fosamax’properly

and/orwhocontinuetotake‘Fosamax’afterdevelopingsymptomssuggestiveofoesophagealirritation.Itisvery

importantthatthefulldosinginstructionsareprovidedto,andunderstoodbythepatient,(see4.2‘Posologyand

methodofadministration’).Patientsshouldbeinformedthatfailuretofollowtheseinstructionsmayincreasetheirrisk

ofoesophagealproblems.

Whilenoincreaseriskwasobservedinextensiveclinicaltrials,therehavebeenrare(post-marketing)reportsofgastric

andduodenalulcers,somesevereandwithcomplications.

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimesincludingprimarilyintravenouslyadministration

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(see4.8undersirableeffects).Thetimetoonsetof

symptomsvariedfromonedaytoseveralmonthsafterstartingtreatment.Mostpatientshadreliefofsymptomsafter

stopping.Asubsethadrecurrenceofsymptomswhenrechallangedwiththesamedrugoranotherbisphosphonate.

‘Fosamax’isnotrecommendedforpatientswithsevererenalinsufficiency(see4.2Posologyandmethodof

administration’).

Causesofosteoporosisotherthanoestrogendeficiency,ageingandglucocorticoiduseshouldbeconsidered.

Hypocalcaemiamustbecorrectedbeforeinitiatingtherapywith‘Fosamax’(see4.3‘Contraindications’).Other

disordersaffectingmineralmetabolism(suchasvitaminDdeficiencyandhypoparathyroidism)shouldalsobe

effectivelytreated.Inpatientswiththeseconditions,serumcalciumandsymptomsofhypocalcaemiashouldbe

monitoredduringtherapywith‘Fosamax’.

Duetothepositiveeffectsof‘Fosamax’inincreasingbonemineral,small,asymptomaticdecreasesinserumcalcium

andphosphatemayoccur,especiallyinpatientsreceivingglucocorticoids,inwhomcalciumabsorptionmaybe

decreased.Theseareusuallysmallandasymptomatic.However,therehavebeenrarereportsofsymptomatic

hypocalcemia,whichhaveoccasionallybeensevereandoftenoccurredinpatientswithpredisposingconditions(e.g.

hypoparathyroidism,vitaminDdeficiencyandcalciummalabsorption).EnsuringadequatecalciumandvitaminD

intakeisthereforeparticularlyimportantinpatientsreceivingglucocorticoids.

Excipients:

Thismedicinalproductcontainslactose.Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapp

lactasedeficiencyorglucose-galactosemalabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Iftakenatthesametime,itislikelythatcalciumsupplements,antacids,andotheroralmedicationswillinterferewith

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otheroralmedication.

Nootherdruginteractionsofclinicalsignificanceareanticipated.

Nootherinteractionswithmedicinalproductsofclinicalsignificanceareanticipated.Anumberofpatientsinthe

clinicaltrialsreceivedostrogen(intravaginal,transdermal,ororal)whiletakingalendronate.Noadverseexperiences

attributabletotheirconcomitantusewereidentified.

SinceNSAIDuseisassociatedwithgastrointestinalirritation,cautionshouldbeusedduringconcomitantusewith

alendronate.

Althoughspecificinteractionstudieswerenotperformed,inclinicalstudiesalendronatewasusedconcomitantlywitha

widerangeofcommonlyprescribedmedicinalproductswithoutevidenceofclinicaladverseinteractions.

4.6Fertility,pregnancyandlactation

Useduringpregnancy

‘Fosamax’shouldnotbeusedduringpregnancy.Therearenoadequatedatafromtheuseofalendronateinpregnant

women.Animalstudiesdonotindicatedirectharmfuleffectswithrespecttopregnancy,embryonic/fetaldevelopment,

orpostnataldevelopment.Alendronategivenduringpregnancyinratscauseddystociarelatedtohypocalcemia(see5.3

'Preclinicalsafetydata')

Useduringlactation

Itisnotknownwhether‘Fosamax’isexcretedintohumanbreastmilk.Fosomaxshouldnotbeusedbybreast-feeding

women.

4.7Effectsonabilitytodriveandusemachines

Nostudiesontheabilitytodriveandusemachineshavebeenperformed.However,certainadversereactionsthathave

beenreportedwith'Fosamax'mayaffectsomepatients'abilitytodriveoroperatemachinery.Individualresponsesto

'Fosamax'mayvary.(See4.8Undesirableeffects).

4.8Undesirableeffects

‘Fosamax’hasbeenstudiedinninemajorclinicalstudies(n=5,886).Inthelongestrunningtrialsinpost-menopausal

womenuptofiveyearsexperiencehasbeencollected.Twoyearssafetydataareavailableinbothmenwith

osteoporosisandmenandwomenonglucocorticoids.

Thefollowingadverseexperienceshavealsobeenreportedduringclinicalstudiesand/orpost-marketinguse:

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

isolatedcases)]

Immunesystemdisorders:

Rare:hypersensitivityreactionsincludingurticariaandangioedema

Metabolismandnutritiondisorders:

Rare:symptomatichypocalcaemia,ofteninassociationwithpredisposingconditions.(seesection4.4)

Nervoussystemdisorders:

Common:headache

Eyedisorders:

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Gastrointestinaldisorders:

Common:abdominalpain,dyspepsia,constipation,diarrhoea,flatulence,oesophageal,ulcer*,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,corticosteroids,poororalhygienearealsodeemedasriskfactors;severemusculoskeletal

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

Generaldisordersandadministrativesiteconditions:

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

withinitiationoftreatment.

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyunknown):

Nervoussystemdisorders:dizziness,dysgeusia

Earandlabyrinthdisorders:vertigo

Skinandsubcutaneoustissuedisorders:alopecia

Musculoskeletal,connectivetissueandbonedisorders:jointswelling

Generaldisordersandadministrativesiteconditions:asthenia,peripheraloedema

Laboratorytestfindings

Inclinicalstudies,asymptomatic,mildandtransientdecreasesinserumcalciumandphosphatewereobservedin

approximately18%and10%,respectively,ofpatientstaking‘Fosamax’versusapproximately12%and3%ofthose

takingplacebo.However,theincidencesofdecreasesinserumcalciumto<2.0mmol/landserumphosphateto ≤0.65

mmol/lweresimilarinbothtreatmentgroups.

4.9Overdose

Significantlethalityaftersingleoraldoseswasseeninfemaleratsandmiceat552mg/kg(3,256mg/m 2

)and966

mg/kg(2,898mg/m 2

)(2,760and4,830*timesincludetherecommendeddoseforthetreatmentofosteoporosisinpost-

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

Therewasnolethalityindogsatoraldosesupto200mg/kg(4,000mg/m 2

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thetreatmentofosteoporosisinpost-menopausalwomen).

Nospecificinformationisavailableonthetreatmentofoverdosagewith‘Fosamax’.Hypocalcaemia,

hypophosphataemiaanduppergastro-intestinaladverseevents,suchasupsetstomach,heartburn,oesophagitis,

gastritis,orulcer,mayresultfromoraloverdosage.Milkorantacidsshouldbegiventobindalendronate.Owingto

theriskofoesophagealirritation,vomitingshouldnotbeinducedandthepatientshouldremainfullyupright.

*Basedonapatientweightof50kg

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

‘Fosamax’isabisphosphonatethatinhibitsosteoclasticboneresorptionwithnodirecteffectonboneformation.The

boneformedduringtreatmentwith‘Fosamax’isofnormalquality.

Treatmentofpost-menopausalosteoporosis:

Theeffectsof‘Fosamax’onbonemassandfractureincidenceinpost-menopausalwomenwereexaminedintwoinitial

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

Intheinitialefficacystudies,themeanbonemineraldensity(BMD)increaseswith‘Fosamax’10mg/dayrelativeto

placeboatthreeyearswere8.8%,5.9%and7.8%atthespine,femoralneckandtrochanter,respectively.Totalbody

BMDalsoincreasedsignificantly.Therewasa48%reductionintheproportionofpatientstreatedwith‘Fosamax’

experiencingoneormorevertebralfracturesrelativetothosetreatedwithplacebo.Inthetwo-yearextensionofthese

studiesBMDatthespineandtrochantercontinuedtoincreaseandBMDatthefemoralneckandtotalbodywere

maintained.

FITconsistedoftwoplacebo-controlledstudies:athree-yearstudyof2,027patientswhohadatleastonebaseline

vertebral(compression)fractureandafour-yearstudyof4,432patientswithlowbonemassbutwithoutabaseline

vertebralfracture,37%ofwhomhadosteoporosisasdefinedbyabaselinefemoralneckBMDatleast2.5standard

deviationsbelowthemeanforyoung,adultwomen.InallFITpatientswithosteoporosisfrombothstudies,‘Fosamax’

reducedtheincidenceof: ≥1vertebralfractureby48%,multiplevertebralfracturesby87%,≥1painfulvertebral

fractureby45%,anypainfulfractureby31%andhipfractureby54%.

Overalltheseresultsdemonstratetheconsistenteffectof‘Fosamax’toreducetheincidenceoffractures,including

thoseofthespineandhip,whicharethesitesofosteoporoticfractureassociatedwiththegreatestmorbidity.

Preventionofpost-menopausalosteoporosis:

Theeffectsof‘Fosamax’topreventbonelosswereexaminedintwostudiesofpost-menopausalwomenaged ≤60

years.Inthelargerstudyof1,609women( ≥6monthspost-menopausal)thosereceiving‘Fosamax’5mgdailyfortwo

yearshadBMDincreasesof3.5%,1.3%,3.0%and0.7%atthespine,femoralneck,trochanterandtotalbody,

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

treatedwith‘Fosamax’5mgdailyforthreeyears.Incontrast,inbothstudies,womenreceivingplacebolostbone

massatarateofapproximately1%peryear.Thelongertermeffectsof‘Fosamax’inanosteoporosisprevention

populationarenotknownbutclinicaltrialextensionsofupto10yearsofcontinuoustreatmentarecurrentlyin

progress.

Concomitantusewithoestrogen/hormonereplacementtherapy(HRT):

TheeffectsonBMDoftreatmentwith‘Fosamax’10mgonce-dailyandconjugatedoestrogen(0.625mg/day)either

aloneorincombinationwereassessedinatwo-yearstudyofhysterectomised,post-menopausal,osteoporoticwomen.

Attwoyears,theincreasesinlumbarspineBMDfrombaselineweresignificantlygreaterwiththecombination(8.3%)

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TheeffectsofBMDwhen‘Fosamax’wasaddedtostabledoses(foratleastoneyear)ofHRT(oestrogen±progestin)

wereassessedinaone-yearstudyinpost-menopausal,osteoporoticwomen.Theadditionof‘Fosamax’10mgonce-

dailytoHRTproduced,atoneyear,significantlygreaterincreasesinlumbarspineBMD(3.7%)vs.HRTalone(1.1%).

Inthesestudies,significantincreasesorfavourabletrendsinBMDforcombinedtherapycomparedwithHRTalone

wereseenatthetotalhip,femoralneckandtrochanter.NosignificanteffectwasseenfortotalbodyBMD.

Treatmentofosteoporosisinmen

Theefficacyof‘Fosamax’10mgoncedailyinmen(ages31to87;mean,63)withosteoporosiswasdemonstratedina

two-yearstudy.Attwoyears,themeanincreasesrelativetoplaceboinBMDinmenreceiving‘Fosamax’10mg/day

were:lumbarspine,5.3%;femoralneck,2.6%;trochanter,3.1%;andtotalbody,1.6%.‘Fosamax’waseffective

regardlessofage,race,gonadalfunction,baselinerateofboneturnover,orbaselineBMD.Consistentwithmuch

largerstudiesinpost-menopausalwomen,inthesemen,‘Fosamax’10mg/dayreducedtheincidenceofnewvertebral

fracture(assessedbyquantitativeradiography)relativetoplacebo(0.8%vs.7.1%)and,correspondingly,alsoreduced

heightloss(-0.6vs.2.4mm).

Glucocorticoid-inducedosteoporosis:

Theefficacyof‘Fosamax’5and10mgonce-dailyinmenandwomenreceivingatleast7.5mg/dayofprednisone(or

equivalent)wasdemonstratedintwo,one-yearstudies.Atoneyear,themeanincreasesrelativetoplaceboinBMDin

patientsreceiving‘Fosamax’5mg/dayfromthecombinedstudieswere:lumbarspine,2.4%;femoralneck,2.2%;and

trochanter,1.6%.TotalbodyBMDwasmaintainedwiththisdoseof‘Fosamax’.TheincreasesinBMDwith

‘Fosamax’10mg/dayweresimilartothosewith‘Fosamax’5mg/dayinallpatientsexceptforthosepost-menopausal

womennotreceivingoestrogentherapy.Inthesewomen,theincreases(relativetoplacebo)with‘Fosamax’10mg/day

weregreaterthanthosewith‘Fosamax’5mg/dayatthelumbarspine(4.1%vs.1.6%)andtrochanter(2.8%vs.1.7%),

butnotatothersites.‘Fosamax’waseffectiveregardlessofdoseordurationofglucocorticoiduse.

Themajorityofpatientsfromthesestudieswhoremainedonatleast7.5mg/dayofprednisoneorequivalentcontinued

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

with‘Fosamax’5and10mg/dayrespectively.SignificantincreasesinBMD(relativetoplacebo)werealsoobserved

atthefemoralneck,trochanter,andtotalbody.

Whenthedatafromthethreedosagegroups(5or10mgfortwoyearsor2.5mgforoneyearfollowedby10mgfor

oneyear)waspooled,therewasasignificantreductionintheincidenceofpatientswithanewvertebralfractureattwo

years(‘Fosamax’,0.7%vsplacebo,6.8%).

5.2Pharmacokineticproperties

Absorption

Relativetoanintravenous(IV)referencedose,theoralbioavailabilityofalendronateinwomenwas0.7%fordoses

rangingfrom5to40mgwhenadministeredafteranovernightfastandtwohoursbeforeastandardisedbreakfast.Oral

bioavailabilityinmen(0.6%)wassimilartothatinwomen.Bioavailabilitywasdecreasedsimilarly(byapproximately

40%)whetheralendronatewasadministeredonehourorhalfanhourbeforeastandardisedbreakfast.Inosteoporosis

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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[14C]alendronate,approximately50%oftheradioactivitywasexcretedintheurine

within72hoursandlittleornoradioactivitywasrecoveredinthefaeces.Followingasingle10mgIVdose,therenal

clearanceofalendronatewas71ml/min,andsystemicclearancedidnotexceed200ml/min.Plasmaconcentrationsfell

bymorethan95%within6hoursfollowingIVadministration.Theterminalhalf-lifeinhumansisestimatedtoexceed

tenyears,reflectingreleaseofalendronatefromtheskeleton.Alendronateisnotexcretedthroughtheacidicorbasic

transportsystemsofthekidneyinrats,andthusitisnotanticipatedtointerferewiththeexcretionofotherdrugsby

thosesystemsinhumans.

Characteristicsinpatients

Preclinicalstudiesshowthatthedrugnotdepositedinboneisrapidlyexcretedintheurine.Noevidenceofsaturation

ofboneuptakewasfoundafterchronicdosingwithcumulativeIVdosesupto35mg/kginanimals.Althoughno

clinicalinformationisavailable,itislikelythat,asinanimals,eliminationofalendronateviathekidneywillbe

reducedinpatientswithimpairedrenalfunction.Therefore,somewhatgreateraccumulationofalendronateinbone

mightbeexpectedinpatientswithimpairedrenalfunction(see4.2‘Posologyandmethodofadministration’).

5.3Preclinicalsafetydata

Noadditionalrelevantinformation.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Anhydrouslactose

Croscarmellosesodium

Magnesiumstearate

Carnaubawax

6.2Incompatibilities

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6.3ShelfLife

2years.

6.4Specialprecautionsforstorage

Donotstoreabove30 °

6.5Natureandcontentsofcontainer

BlisterpacksofopaquePVCliddedwithanaluminiumfoil.

Packsize:28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

MerckSharp&DohmeLimited

HertfordRoad

Hoddesdon

HertfordshireEN119BU

UnitedKingdom

8MARKETINGAUTHORISATIONNUMBER

PA35/83/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:08January1996

Dateoflastrenewal:08January2006

10DATEOFREVISIONOFTHETEXT

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