ALENDRONIC ACID ONCE WEEKLY

Main information

  • Trade name:
  • ALENDRONIC ACID ONCE WEEKLY
  • Dosage:
  • 70 Milligram
  • Pharmaceutical form:
  • Tablets
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ALENDRONIC ACID ONCE WEEKLY
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA1271/006/001
  • Authorization date:
  • 04-06-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AlendronicAcidOnceWeekly70mgTablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Eachtabletcontainstheequivalentof70mgofalendronicacid(as91.37mgalendronatemonosodiumtrihydrate).

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Tablet.

Whiteovalflattablets,withdimensionsof14x8mmandmarkedononefacewith“70”

4CLINICALPARTICULARS

4.1TherapeuticIndications

Treatmentofpostmenopausalosteoporosis.Sodiumalendronatereducestheriskofvertebralandhipfractures.

4.2Posologyandmethodofadministration

Therecommendeddosageisone70mgtabletonceweekly.

Topermitadequateabsorptionofalendronate:

Sodiumalendronatemustbetakenatleast30minutesbeforethefirstfood,beverage,ormedicinalproductoftheday

withplainwateronly.Otherbeverages(includingmineralwater),foodandsomemedicinalproductsarelikelyto

reducetheabsorptionofalendronate(see4.5'Interactionwithothermedicinalproductsandotherformsofinteraction').

Tofacilitatedeliverytothestomachandthusreducethepotentialforlocalandoesophagealirritation/adverse

experiences(see4.4'Specialwarningsandprecautionsforuse'):

Sodiumalendronateshouldonlybeswalloweduponarisingforthedaywithafullglassofwater(notlessthan

200mlor7fl.oz.).

Patientsshouldnotchewthetabletorallowthetablettodissolveintheirmouthsbecauseofapotentialfor

oropharyngealulceration.

Patientsshouldnotliedownuntilaftertheirfirstfoodofthedaywhichshouldbeatleast30minutesaftertaking

thetablet.

Patientsshouldnotliedownforatleast30minutesaftertakingSodiumalendronate.

Sodiumalendronateshouldnotbetakenatbedtimeorbeforearisingfortheday.

PatientsshouldreceivesupplementalcalciumandvitaminDifdietaryintakeisinadequate(see4.4'Specialwarnings

andprecautionsforuse').

Useintheelderly:Inclinicalstudiestherewasnoage-relateddifferenceintheefficacyorsafetyprofilesof

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Useinrenalimpairment:NodosageadjustmentisnecessaryforpatientswithGFRgreaterthan35ml/min.Alendronate

isnotrecommendedforpatientswithrenalimpairmentwhereGFRislessthan35ml/min,duetolackofexperience.

Useinchildren:Alendronatehasbeenstudiedinasmallnumberofpatientswithosteogenesisimperfectaunder18

yearsofage.Resultsareinsufficienttosupportitsuseinchildren.

Sodiumalendronate70mgTabletshavenotbeeninvestigatedinthetreatmentofglucocorticoid-inducedosteoporosis.

4.3Contraindications

Abnormalitiesoftheoesophagusandotherfactorswhichdelayoesophagealemptyingsuchasstrictureorachalasia.

Inabilitytostandorsituprightforatleast30minutes.

Hypersensitivitytoalendronateortoanyoftheexcipients.

Hypocalcaemia.

Seealso4.4'Specialwarningsandprecautionsforuse'.

4.4Specialwarningsandprecautionsforuse

Alendronatecancauselocalirritationoftheuppergastro-intestinalmucosa.Becausethereisapotentialforworsening

oftheunderlyingdisease,cautionshouldbeusedwhenalendronateisgiventopatientswithactiveuppergastro-

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

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

surgeryoftheuppergastro-intestinaltractotherthanpyloroplasty(see4.3'Contra-indications').

Oesophagealreactions(sometimessevereandrequiringhospitalisation),suchasoesophagitis,oesophagealulcersand

oesophagealerosions,rarelyfollowedbyoesophagealstricture,havebeenreportedinpatientsreceivingalendronate.

Physiciansshouldthereforebealerttoanysignsorsymptomssignallingapossibleoesophagealreactionandpatients

shouldbeinstructedtodiscontinuealendronateandseekmedicalattentioniftheydevelopsymptomsofoesophageal

irritationsuchasdysphagia,painonswallowingorretrosternalpain,neworworseningheartburn.

Theriskofsevereoesophagealadverseexperiencesappearstobegreaterinpatientswhofailtotakealendronate

properlyand/orwhocontinuetotakealendronateafterdevelopingsymptomssuggestiveofoesophagealirritation.Itis

veryimportantthatthefulldosinginstructionsareprovidedto,andunderstoodbythepatient(see4.2'Posologyand

methodofadministration').Patientsshouldbeinformedthatfailuretofollowtheseinstructionsmayincreasetheirrisk

ofoesophagealproblems.

Whilenoincreasedriskwasobservedinextensiveclinicaltrials,therehavebeenrare(post-marketing)reportsof

gastricandduodenalulcers,somesevereandwithcomplications.Acausalrelationshipcannotberuledout.

PatientsshouldbeinstructedthatiftheymissadoseofSodiumalendronate70mg,theyshouldtakeonetabletonthe

morningaftertheyremember.Theyshouldnottaketwotabletsonthesamedaybutshouldreturntotakingonetablet

onceaweek,asoriginallyscheduledontheirchosenday.

AlendronateisnotrecommendedforpatientswithrenalimpairmentwhereGFRislessthan35ml/min,(see4.2

'Posologyandmethodofadministration').

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Hypocalcaemiamustbecorrectedbeforeinitiatingtherapywithalendronate(see4.3'Contra-indications').Other

disordersaffectingmineralmetabolism(suchasvitaminDdeficiencyandhypoparathyroidism)shouldalsobe

effectivelytreated.Inpatientswiththeseconditions,serumcalciumandsymptomsofhypocalcaemiashouldbe

monitoredduringtherapywithSodiumalendronate.

Duetopositiveeffectsofalendronateinincreasingbonemineral,decreasesinserumcalciumandphosphatemay

occur.Theseareusuallysmallandasymptomatic.However,therehavebeenreportsofsymptomatichypocalcaemia,

whichoccasionallyhavebeensevereandoftenoccurredinpatientswithpredisposingconditions(e.g.

hypoparathyroidism,vitaminDdeficiencyandcalciummalabsorption).EnsuringadequatecalciumandvitaminD

intakeisthereforeparticularlyimportantinpatientsreceivingglucocorticoids.

Osteonecrosisofthejaw,generallyassociatedwithtoothextractionand/orlocalinfection(includingosteomyelitis)has

beenreportedinpatientswithcancerreceivingtreatmentregimensincludingprimarilyintravenouslyadministered

bisphosphonates.Manyofthesepatientswerealsoreceivingchemotherapywithcorticosteriods.Osteonecrosisofthe

jawhasalsobeenreportedinpatientswithosteoporosisreceivingoralbisphosphonates.

Adentalexaminationwithappropriatepreventivedentistryshouldbeconsideredpriortotreatmentwith

bisphosphonatesinpatientswithconcomitantriskfactors(e.gcancer,chemotherapy,radiotherapy,corticosteriods,

poororalhygiene).

Whileontreatment,thesepatientsshouldavoidinvasivedentalproceduresifpossible.Forpatientswhodevelop

osteonecrosisofthejawwhileonbisphosphonatestherapy,dentalsurgerymayexacerbatethecondition.Forpatients

requiringdentalprocedures,therearenodataavailabletosuggestwhetherdiscontinuationofbisphosphonatetreatment

reducestheriskofosteonecrosisofthejaw.

Clinicaljudgementofthetreatingphysicianshouldguidethemanagementplanofeachpatientbasedonindividual

benefit/riskassessment.

Bone,jointand/ormusclepainhasbeenreportedinpatientstakingbisphosphonates.Inpost-marketingexperience,

thesesymptomshaverarelybeensevereand/orincapacitating(seesection4.8).Thetimetoonsetofsymptomsvaried

fromonedaytoseveralmonthsafterstartingtreatment.Mostpatientshadreliefofsymptomsafterstopping.Asubset

hadrecurrenceofsymptomswhenrechallengedwiththesamedrugoranotherbisphosphonate.

Stressfractures(alsoknownasinsufficiencyfractures)oftheproximalfemoralshafthavebeenreportedinpatients

treatedlong-termwithalendronicacid(timetoonsetinthemajorityofcasesrangedfrom18monthsto10years).The

fracturesoccurredafterminimalornotraumaandsomepatientsexperiencedthighpain,oftenassociatedwithimaging

featuresofstressfractures,weekstomonthsbeforepresentingwithacompletedfemoralfracture.Fractureswereoften

bilateral;thereforethecontralateralfemurshouldbeexaminedinbisphosphonate-treatedpatientswhohavesustaineda

femoralshaftfracture.Poorhealingofthesefractureswasalsoreported.Discontinuationofbisphosphonatetherapyin

patientswithstressfractureisadvisablependingevaluationofthepatient,basedonanindividualbenefitrisk

assessment.

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.

Althoughspecificinteractionstudieswerenotperformed,inclinicalstudiesalendronatewasusedconcomitantlywitha

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4.6Fertility,pregnancyandlactation

Therearenoadequatedatafromtheuseofalendronatemonosodiumtrihydrateinpregnantwomen.Animalstudiesdo

notindicatedirectharmfuleffectswithrespecttopregnancy,embryonal/foetaldevelopment,orpostnataldevelopment.

Alendronategivenduringpregnancyinratscauseddystociarelatedtohypocalcemia(see5.3'Preclinicalsafetydata').

Giventheindication,alendronateshouldnotbeusedduringpregnancy.

Itisnotknownwhetheralendronateisexcretedintohumanbreastmilk.Giventheindication,alendronateshouldnotbe

usedbybreast-feedingwomen.

4.7Effectsonabilitytodriveandusemachines

Noeffectsonabilitytodriveandusemachineshavebeenobserved.

4.8Undesirableeffects

Inaone-yearstudyinpost-menopausalwomenwithosteoporosistheoverallsafetyprofilesof'Fosamax'OnceWeekly

70mg(n=519)andalendronate10mg/day(n=370)weresimilar.

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

n=397)theoverallsafetyprofilesofalendronate10mg/dayandplaceboweresimilar.

Adverseexperiencesreportedbytheinvestigatorsaspossibly,probablyordefinitelydrug-relatedarepresentedbelow

iftheyoccurredin>1%ineithertreatmentgroupintheone-yearstudy,orin>1%ofpatientstreatedwithalendronate

10mg/dayandatagreaterincidencethaninpatientsgivenplacebointhethree-yearstudies:

One-YearStudy Three-YearStudies

'Fosamax'

OnceWeekly

70mg

(n=519) Alendronate

10mg/day

(n=370) Alendronate

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, 2.9 3.2 4.1 2.5

muscleorjoint)pain

musclecramp 0.2 1.1 0.0 1.0

Neurological

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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)(see

section4.4)

*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(see4.4'Specialwarningsandprecautionsforuse').

Generaldisordersandadministrationsiteconditions:

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

withinitiationoftreatment.

Duringpost-marketingexperiencethefollowingreactionshavebeenreported(frequencyunknown):

Nervoussystemdisorders:dizziness,dysgeusia

Earandlabyrinthdisorders:vertigo

Skinandsubcutaneoustissuedisorders:alopecia

Musculoskeletal,connectivetissueandbonedisorders:jointswelling,stressfracturesoftheproximalfemoralshaft

(seesection4.4).

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Laboratorytestfindings

Inclinicalstudies,asymptomatic,mildandtransientdecreasesinserumcalciumandphosphatewereobservedin

approximately18and10%,respectively,ofpatientstakingalendronate10mg/dayversusapproximately12and3%of

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

phosphateto<2.0mg/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:Bisphosphonate,forthetreatmentofbonediseases.

ATCCode:M05BA04

TheactiveingredientofSodiumalendronate70mgTablets,alendronatemonosodiumtrihydrate,isabisphosphonate

thatinhibitsosteoclasticboneresorptionwithnodirecteffectonboneformation.Preclinicalstudieshaveshown

preferentiallocalisationofalendronatetositesofactiveresorption.

Activityofosteoclastsisinhibited,butrecruitmentorattachmentofosteoclastsisnotaffected.Theboneformedduring

treatmentwithalendronateisofnormalquality.

Treatmentofpost-menopausalosteoporosis

OsteoporosisisdefinedasBMDofthespineorhip2.5SDbelowthemeanvalueofanormalyoungpopulation

orasapreviousfragilityfracture,irrespectiveofBMD.

ThetherapeuticequivalenceofAlendronicAcidOnceWeekly70mg(n=519)andalendronate10mgdaily(n=370)

wasdemonstratedinaone-yearmulticentrestudyofpost-menopausalwomenwithosteoporosis.Themeanincreases

frombaselineinlumbarspineBMDatoneyearwere5.1%(95%CI:4.8,5.4%)inthe70mgonce-weeklygroupand

5.4%(95%CI:5.0,5.8%)inthe10mgdailygroup.ThemeanBMDincreaseswere2.3%and2.9%atthefemoralneck

and2.9%and3.1%atthetotalhipinthe70mgonceweeklyand10mgdailygroups,respectively.Thetwotreatment

groupswerealsosimilarwithregardtoBMDincreasesatotherskeletalsites.

Theeffectsofalendronateonbonemassandfractureincidenceinpost-menopausalwomenwereexaminedintwo

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

Intheinitialefficacystudies,themeanbonemineraldensity(BMD)increaseswithalendronate10mg/dayrelativeto

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

BMDalsoincreasedsignificantly.Therewasa48%reduction(alendronate3.2%vsplacebo6.2%)intheproportionof

patientstreatedwithalendronateexperiencingoneormorevertebralfracturesrelativetothosetreatedwithplacebo.In

thetwo-yearextensionofthesestudiesBMDatthespineandtrochantercontinuedtoincreaseandBMDatthefemoral

neckandtotalbodyweremaintained.

FITconsistedoftwoplacebo-controlledstudiesusingalendronatedaily(5mgdailyfortwoyearsand10mgdailyfor

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FIT1:Athree-yearstudyof2,027patientswhohadatleastonebaselinevertebral(compression)fracture.Inthis

studyalendronatedailyreducedtheincidenceof1newvertebralfractureby47%(alendronate7.9%vs.placebo

15.0%).Inaddition,astatisticallysignificantreductionwasfoundintheincidenceofhipfractures(1.1%vs.2.2%,a

reductionof51%).

FIT2:Afour-yearstudyof4,432patientswithlowbonemassbutwithoutabaselinevertebralfracture.Inthisstudy,

asignificantdifferencewasobservedintheanalysisofthesubgroupofosteoporoticwomen(37%oftheglobal

populationwhocorrespondwiththeabovedefinitionofosteoporosis)intheincidenceofhipfractures(alendronate

1.0%vs.placebo2.2%,areductionof56%)andintheincidenceof1vertebralfracture(2.9%vs.5.8%,areductionof

50%).

5.2Pharmacokineticproperties

Absorption

Relativetoanintravenousreferencedose,theoralmeanbioavailabilityofalendronateinwomenwas0.64%fordoses

rangingfrom5to70mgwhenadministeredafteranovernightfastandtwohoursbeforeastandardisedbreakfast.

Bioavailabilitywasdecreasedsimilarlytoanestimated0.46%and0.39%whenalendronatewasadministeredonehour

orhalfanhourbeforeastandardisedbreakfast.Inosteoporosisstudies,alendronatewaseffectivewhenadministeredat

least30minutesbeforethefirstfoodorbeverageoftheday.

Bioavailabilitywasnegligiblewhetheralendronatewasadministeredwith,oruptotwohoursafter,astandardised

breakfast.Concomitantadministrationofalendronatewithcoffeeororangejuicereducedbioavailabilityby

approximately60%.

Inhealthysubjects,oralprednisone(20mgthreetimesdailyforfivedays)didnotproduceaclinicallymeaningful

changeinoralbioavailabilityofalendronate(ameanincreaserangingfrom20%to44%).

Distribution

Studiesinratsshowthatalendronatetransientlydistributestosofttissuesfollowing1mg/kgintravenousadministration

butisthenrapidlyredistributedtoboneorexcretedintheurine.Themeansteady-statevolumeofdistribution,

exclusiveofbone,isatleast28litresinhumans.Concentrationsofdruginplasmafollowingtherapeuticoraldosesare

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

Biotransformation

Thereisnoevidencethatalendronateismetabolisedinanimalsorhumans.

Elimination

Followingasingleintravenousdoseof[ 14

C]alendronate,approximately50%oftheradioactivitywasexcretedinthe

urinewithin72hoursandlittleornoradioactivitywasrecoveredinthefaeces.Followingasingle10mgintravenous

dose,therenalclearanceofalendronatewas71ml/min,andsystemicclearancedidnotexceed200ml/min.Plasma

concentrationsfellbymorethan95%withinsixhoursfollowingintravenousadministration.Theterminalhalf-lifein

humansisestimatedtoexceedtenyears,reflectingreleaseofalendronatefromtheskeleton.Alendronateisnot

excretedthroughtheacidicorbasictransportsystemsofthekidneyinrats,andthusitisnotanticipatedtointerfere

withtheexcretionofothermedicinalproductsbythosesystemsinhumans.

Characteristicsinpatients

Preclinicalstudiesshowthatthedrugthatisnotdepositedinboneisrapidlyexcretedintheurine.Noevidenceof

saturationofboneuptakewasfoundafterchronicdosingwithcumulativeintravenousdosesupto35mg/kginanimals.

Althoughnoclinicalinformationisavailable,itislikelythat,asinanimals,eliminationofalendronateviathekidney

willbereducedinpatientswithimpairedrenalfunction.Therefore,somewhatgreateraccumulationofalendronatein

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5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityandcarcinogenicpotential.Studiesinratshaveshownthattreatmentwithalendronate

duringpregnancywasassociatedwithdystociaindamsduringparturitionwhichwasrelatedtohypocalcaemia.In

studies,ratsgivenhighdosesshowedanincreasedincidenceofincompletefoetalossification.Therelevancetohumans

isunknown.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Crospovidone

Magnesiumstearate

6.2Incompatibilities

Notapplicable.

6.3Shelflife

3years

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

6.5Natureandcontentsofcontainer

Alu/PVC/PVDCblisters

Packsize:4tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7MARKETINGAUTHORISATIONHOLDER

LaboratoriosDavurS.L.U.

C/AnabelSegura11

EdificioAlbatrosB

1aplanta

Alcobendas

28108Madrid

Spain

8MARKETINGAUTHORISATIONNUMBER

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9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:22ndJune2007

10DATEOFREVISIONOFTHETEXT

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