ADALAT LA

Main information

  • Trade name:
  • ADALAT LA
  • Dosage:
  • 30 Milligram
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • ADALAT LA
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1500/037/002
  • Authorization date:
  • 08-01-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACT1995,asamended

MedicinalProducts(ControlofPlacingontheMarket)Regulations,2007,asamended

PPA1500/037/002

CaseNo:2083758

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

ProfindWholesaleLtd.

Unit625,KilshaneAvenue,NorthwestBusinessPark,Dublin15,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

AdalatLA30mgProlonged-ReleaseTablet

theparticularsofwhicharesetoutintheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsasmaybespecifiedin

thesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom28/07/2010.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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Date Printed 28/07/2010 CRN 2083758 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AdalatLA30mgProlonged-ReleaseTablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains30mgnifedipine.

Excipients:Sodium

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Prolonged-releasefilmcoatedtablet

ProductimportedfromItaly

Pink,circularconvextabletswithAdalat30markedononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthetreatmentofallgradesofhypertension.

Forthemanagementofchronicstableanginapectoriseitherasmonotherapyorincombinationwithabeta-blocker.

4.2Posologyandmethodofadministration

Fororaladministration,thetabletsshouldbeswallowedwholewithaglassofwater,independentofmeals.Thetablets

shouldbetakenatapproximately24-hourintervals,i.e.atthesametimeeachday,preferablyduringthemorning.

AdalatLAtabletsmustbeswallowedwhole;undernocircumstancesshouldtheybebitten,chewedorbrokenup.

Inmildtomoderatehypertension,therecommendedinitialdoseisone20mgtabletonce-daily.Insevere

hypertension,therecommendedinitialdoseisone30mgtabletonce-daily.Ifnecessary,thedosagecanbeincreased

accordingtoindividualrequirementsuptoamaximumof90mgonce-daily.

Forthemanagementofanginapectoris,therecommendedinitialdoseisone30mgtabletonce-daily.Thedosagecan

beincreasedaccordingtoindividualrequirementsuptoamaximumof90mgonce-daily.

PatientsinwhomhypertensionoranginalsymptomsarecontrolledonAdalatcapsulesorAdalatretardmaybesafely

switchedtoAdalatLA.Prophylacticanti-anginalefficacyismaintainedwhenpatientsareswitchedfromothercalcium

antagonistssuchasdiltiazemorverapamiltoAdalatLA.Patientsswitchedfromothercalciumantagonistsshould

initiatetherapyattherecommendedinitialdoseof30mgAdalatLAonce-daily.Subsequenttitrationtoahigherdose

maybeinitiatedaswarrantedclinically.

Thepharmacokineticsofnifedipinearealteredintheelderlysothatlowermaintenancedosesofnifedipinemaybe

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Co-administrationwithCYP3A4inhibitorsorCYP3A4inducersmayresultintherecommendationtoadaptthe

nifedipinedoseornottousenifedipineatall(seeSection4.5).

Patientswithrenalimpairmentshouldnotrequireadjustmentofdosage.

Treatmentmaybecontinuedindefinitely.

Nifedipineisnotrecommendedforuseinchildren.

AdalatLAshouldnotbetakenwithgrapefruitjuice(seeSection4.5).

4.3Contraindications

AdalatLAshouldnotbeadministeredtopatientswithknownhypersensitivitytonifedipineorotherdihydropyridines

becauseofthetheoreticalriskofcross-reactivity.

AdalatLAshouldnotbeadministeredduringpregnancyortonursingmothers.

AdalatLAshouldnotbeusedincardiogenicshock,clinicallysignificantaorticstenosis,unstableangina,orduringor

withinonemonthofamyocardialinfarction.

AdalatLAshouldnotbeusedforthetreatmentofacuteattacksofangina.

ThesafetyofAdalatLAinmalignanthypertensionhasnotbeenestablished.

AdalatLAshouldnotbeusedforsecondarypreventionofmyocardialinfarction.

Owingtothedurationofactionoftheformulation,AdalatLAshouldnotbeadministeredtopatientswithhepatic

impairment.

AdalatLAshouldnotbeadministeredtopatientswithahistoryofgastro-intestinalobstruction,oesophageal

obstruction,oranydegreeofdecreasedlumendiameterofthegastro-intestinaltract.

AdalatLAiscontra-indicatedinpatientswithinflammatoryboweldiseaseorCrohn'sdisease.

AdalatLAshouldnotbeadministeredconcomitantlywithrifampicinsinceeffectiveplasmalevelsofnifedipinemay

notbeachievedowingtoenzymeinduction(seeSection4.5).

4.4Specialwarningsandprecautionsforuse

AdalatLAtabletsmustbeswallowedwhole;undernocircumstancesshouldtheybebitten,chewedorbrokenup.

TheoutermembraneoftheAdalatLAtabletisnotdigestedand,therefore,whatappearstobethecompletetabletmay

beseeninthetoiletorassociatedwiththepatient'sstools.

Cautionshouldbeexercisedinpatientswithhypotensionasthereisariskoffurtherreductioninbloodpressure.

AdalatLAmaybeusedincombinationwithbeta-blockingdrugsandotherantihypertensiveagentsbutthepossibility

ofanadditiveeffectresultinginposturalhypotensionshouldbeborneinmind.AdalatLAwillnotpreventpossible

reboundeffectsaftercessationofotherantihypertensivetherapy.

AdalatLAshouldbeusedwithcautioninpatientswhosecardiacreserveispoor.Deteriorationofheartfailurehas

occasionallybeenobservedwithnifedipine.

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Althougha'steal'effecthasnotbeendemonstrated,patientsexperiencingthiseffectshoulddiscontinuenifedipine

therapy.

DiabeticpatientstakingAdalatLAmayrequireadjustmentoftheircontrol.

Indialysispatientswithmalignanthypertensionandhypovolaemia,amarkeddecreaseinbloodpressurecanoccur.

Therearenosafetyandefficacydatafromwell-controlledstudiesinpregnantwomen(seesection4.6).

Animalstudieshaveshownavarietyofembryotoxic,placentotoxicandfetotoxiceffects(seeSection5.3)when

administeredduringandaftertheperiodoforganogenesis.

Whilstnifedipineiscontra-indicatedinpregnancy,particularcaremustbeexercisedwhenadministeringnifedipinein

combinationwithi.v.magnesiumsulphatetopregnantwomen.

Co-administrationofnifedipinewitherythromycin,ketoconazole,itraconazole,fluconazole,fluoxetine,indinavir,

nelfinavir,ritonavir,amprenavirandsaquinavir,maytheoreticallyresultinanincreaseinnifedipineplasma

concentrations.Uponco-administrationwithanyofthesecytochromeP4503A4inhibitors,bloodpressureshouldbe

monitoredand,ifnecessary,areductioninthenifedipinedoseconsidered(seeSection4.5).

AstheoutermembraneoftheAdalatLAtabletisnotdigested,careshouldbeexercisedasobstructivesymptomsmay

occur,particularlyinpatientswithpre-existingseveregastrointestinalnarrowing.Bezoarscanoccurinveryrarecases

andmayrequiresurgicalintervention.

AdalatLAmustnotbeadministeredtopatientswithKockpouch(ileostomyafterproctocolectomy).

Afalsepositiveeffectmaybeexperiencedwhenperformingabariumcontrastx-ray.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Drugsthataffectnifedipine

NifedipineismetabolisedviathecytochromeP4503A4system,locatedbothintheintestinalmucosaandintheliver.

Drugsthatareknowntoeitherinhibitortoinducethisenzymesystemmaythereforealterthefirstpass(after

oraladministration)ortheclearanceofnifedipine.

Theextentaswellasthedurationofinteractionsshouldbetakenintoaccountwhenadministeringnifedipinetogether

withthefollowingdrugs:

Rifampicin:RifampicinstronglyinducesthecytochromeP4503A4system.Uponco-administrationwithrifampicin,

thebioavailabilityofnifedipineisdistinctlyreducedandthusitsefficacyweakened.Theuseofnifedipinein

combinationwithrifampicinisthereforecontraindicated(seesection4.3).

Uponco-administrationofweaktomoderateinhibitorsofthecytochromeP4503A4system(listedimmediately

below),thebloodpressureshouldbemonitoredand,ifnecessary,areductioninthenifedipinedoseconsidered(see

Sections4.2and4.4).Inthemajorityofthesecases,noformalstudiestoassessthepotentialforadruginteraction

betweennifedipineandthedrug(s)listedhavebeenundertaken,thusfar.

Macrolideantibiotics(e.g.,erythromycin):CertainmacrolideantibioticsareknowntoinhibitthecytochromeP450

3A4mediatedmetabolismofotherdrugs.Thereforethepotentialforanincreaseofnifedipineplasmaconcentrations

uponco-administrationofbothdrugscannotbeexcluded(seeSection4.4).

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Anti-HIVproteaseinhibitors(e.g.,ritonavir):Drugsofthisclasshavebeenshowntoinhibitinvitrothecytochrome

P4503A4mediatedmetabolismofnifedipine.Whenadministeredtogetherwithnifedipine,asubstantialincreasein

plasmaconcentrationsofnifedipineduetoadecreasedfirstpassmetabolismandadecreasedeliminationcannotbe

excluded(seeSection4.4).

Azoleanti-mycotics(e.g.,ketoconazole):DrugsofthisclassareknowntoinhibitthecytochromeP4503A4system.

Whenadministeredorallytogetherwithnifedipine,asubstantialincreaseinsystemicbioavailabilityofnifedipinedue

toadecreasedfirstpassmetabolismcannotbeexcluded(seeSection4.4).

Fluoxetine:FluoxetinehasbeenshowntoinhibitinvitrothecytochromeP4503A4mediatedmetabolismofnifedipine.

Thereforeanincreaseofnifedipineplasmaconcentrationsuponco-administrationofbothdrugscannotbe

excluded(seeSection4.4).

Nefazodone:NefazodoneisknowntoinhibitthecytochromeP4503A4mediatedmetabolismofotherdrugs.Therefore

anincreaseinnifedipineplasmaconcentrationsuponco-administrationofbothdrugscannotbeexcluded(seeSection

4.4).

Quinupristin/dalfopristinandcisapride:Simultaneousadministrationofquinupristin/dalfopristinandnifedipine,or

cisaprideandnifedipine,mayleadtoincreasedplasmaconcentrationsofnifedipine(seeSection4.4).

Valproicacid:Asvalproicacidhasbeenshowntoincreasetheplasmaconcentrationsofthestructurallysimilar

calciumchannelblocker,nimodipine,duetoenzymeinhibition,anincreaseinnifedipineplasmaconcentrationsand

henceanincreaseinefficacycannotbeexcluded(seeSection4.4).

Cimetidine:DuetoitsinhibitionofcytochromeP4503A4,cimetidineelevatestheplasmaconcentrationsofnifedipine

andmaypotentiatetheantihypertensiveeffect(seeSection4.4).

Diltiazem:Diltiazemdecreasestheclearanceofnifedipineand,hence,increasesplasmanifedipinelevels.Therefore,

cautionshouldbetakenwhenbothdrugsareusedincombinationandareductionofthenifedipinedosemaybe

necessary.

Furtherstudies

CytochromeP4503A4system-inducinganti-epilepticdrugs,suchasphenytoin,carbamazepineandphenobarbital:

phenytoininducesthecytochromeP4503A4system.Uponco-administrationwithphenytoin,thebioavailabilityof

nifedipineisreducedandthusitsefficacyweakened.Whenbothdrugsareadministeredconcomitantly,theclinical

responsetonifedipineshouldbemonitoredand,ifnecessary,anincreaseofthenifedipinedoseconsidered.Ifthedose

ofnifedipineisincreasedduringco-administrationofbothdrugs,areductionofthenifedipinedoseshouldbe

consideredwhenthetreatmentwithphenytoinisdiscontinued.

Noformalstudieshavebeenperformedtoinvestigatethepotentialinteractionbetweennifedipineandcarbamazepine

orphenobarbital.Asbothdrugshavebeenshowntoreducetheplasmaconcentrationsofthestructurally

similarcalciumchannelblocker,nimodipine,duetoenzymeinduction,adecreaseinnifedipineplasmaconcentrations

andhenceadecreaseinefficacycannotbeexcluded.

Effectsofnifedipineonotherdrugs

Nifedipinemayincreasethebloodpressureloweringeffectofconcomitantappliedantihypertensives,suchas:

diuretics

beta-blockers

ACE-inhibitors

AT-1antagonists

othercalciumantagonists

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PDE5inhibitors

alpha-methyldopa

Whennifedipineisadministeredsimultaneouslywithbeta-receptorblockersthepatientshouldbecarefullymonitored,

sincedeteriorationofheartfailureisalsoknowntodevelopinisolatedcases.

Digoxin:Thesimultaneousadministrationofnifedipineanddigoxinmayleadtoreduceddigoxinclearanceand,hence,

anincreaseintheplasmadigoxinlevel.Thepatientshouldthereforebecheckedforsymptomsofdigoxinoverdosage

asaprecautionand,ifnecessary,theglycosidedoseshouldbereducedtakingaccountoftheplasmaconcentrationof

digoxin.

Quinidine:Whennifedipineandquinidinehavebeenadministeredsimultaneously,loweredquinidinelevels,orafter

discontinuationofnifedipine,adistinctincreaseinplasmaconcentrationsofquinidine,havebeenobserved

inindividualcases.Forthisreason,whennifedipineiseitheradditionallyadministeredordiscontinued,monitoringof

thequinidineplasmaconcentration,andifnecessary,adjustmentofthequinidinedosearerecommended.

Someauthorsreportedincreasedplasmaconcentrationsofnifedipineuponco-administrationofbothdrugs,while

othersdidnotobserveanalterationinthepharmacokineticsofnifedipine.

Thereforethebloodpressureshouldbecarefullymonitored,ifquinidineisaddedtoanexistingtherapywithnifedipine.

Ifnecessary,thedoseofnifedipineshouldbedecreased.

Tacrolimus:TacrolimushasbeenshowntobemetabolisedviathecytochromeP4503A4system.Datarecently

publishedindicatethatthedoseoftacrolimusadministeredsimultaneouslywithnifedipinemaybereducedin

individualcases.Uponco-administrationofbothdrugs,thetacrolimusplasmaconcentrationsshouldbemonitoredand,

ifnecessary,areductioninthetacrolimusdoseconsidered.

Drugfoodinteractions

GrapefruitjuiceinhibitsthecytochromeP4503A4system.Administrationofnifedipinetogetherwithgrapefruitjuice

thusresultsinelevatedplasmaconcentrationsandprolongedactionofnifedipineduetoadecreasedfirst

passmetabolismorreducedclearance.Asaconsequence,thebloodpressureloweringeffectofnifedipinemaybe

increased.Afterregularintakeofgrapefruitjuice,thiseffectmaylastforatleastthreedaysafterthelastingestionof

grapefruitjuice.

Ingestionofgrapefruit/grapefruitjuiceisthereforetobeavoidedwhiletakingnifedipine(seeSection4.2).

Drugsshownnottointeractwithnifedipine

Thefollowingdrugshavebeenshowntohavenoeffectonthepharmacokineticsofnifedipinewhenadministered

concomitantly:ajmaline,aspirin,benazepril,candesartancilexetil,debrisoquine,doxazosin,irbesartan,omeprazole,

orlistat,pantoprazole,ranitidine,rosiglitazone,talinololandtriamterenehydrochlorothiazide.

Otherformsofinteraction

Nifedipinemayincreasethespectrophotometricvaluesofurinaryvanillylmandelicacidfalsely.However,HPLC

measurementsareunaffected.

4.6Pregnancyandlactation

AdalatLAiscontra-indicatedduringpregnancy.

AdalatLAshouldnotbeusedbywomenwhointendtogetpregnantinthenearfuture.

ThesafetyofAdalatLAforuseinhumanpregnancyhasnotbeenestablished.Evaluationofexperimentalanimal

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AdalatLAiscontra-indicatedinbreastfeeding.Nifedipinepassesintothebreastmilk.Asthereisnoexperienceof

possibleeffectsoninfants,breastfeedingshouldfirstbestoppedifnifedipinetreatmentbecomesnecessaryduringthe

breastfeedingperiod.

Insinglecasesofinvitrofertilisationcalciumantagonistslikenifedipinehavebeenassociatedwithreversible

biochemicalchangesinthespermatozoa’sheadsectionthatmayresultinimpairedspermfunction.Inthosemenwho

arerepeatedlyunsuccessfulinfatheringachildbyinvitrofertilisation,andwherenootherexplanationcanbefound,

calciumantagonistslikenifedipineshouldbeconsideredaspossiblecauses.

4.7Effectsonabilitytodriveandusemachines

Reactionstothedrug,whichvaryinintensityfromindividualtoindividual,mayimpairtheabilitytodriveorto

operatemachinery.Thisappliesparticularlyatthestartoftreatment,onchangingthemedicationandincombination

withalcohol.

4.8Undesirableeffects

Adversedrugreactions(ADRs)basedonplacebo-controlledstudieswithnifedipinesortedbyCIOMSIIIcategoriesof

frequency(clinicaltrialdatabase:nifedipinen=2,661;placebon=1,486;status:22Feb2006andtheACTIONstudy:

nifedipinen=3,825;placebon=3,840)arelistedbelow:

ADRslistedunder"common"wereobservedwithafrequencybelow3%withtheexceptionofoedema(9.9%)and

headache(3.9%).ADRsderivedfrompostmarketingreports(status:15Feb2006)areprintedinbolditalic.

Clinical

Description Common

1%to<10% Uncommon

>0.1%to<1% Rare

>0.01%to<0.1% VeryRare

<0.01%

ImmuneSystemDisorder

Acute

hypersensitivity

reactions Allergicreaction

Allergic

oedema/angioedema Pruritus

Urticaria

Rash Anaphylactic/

anaphylactoid

reaction

PsychiatricDisorders

Behavioural

disturbancesand

sleepdisorders Anxietyreactions

Sleepdisorders

NervousSystemDisorders

Unspecific

cerebrovascular

symptoms Headache Vertigo

Migraine

Unspecific

neurological

symptoms Dizziness

Tremor

Unspecificaltered

peripheral

perception Par/dysaesthesia

EyeDisorders

Unspecificeye

disorders Visualdisturbances

CardiacDisorders

Unspecific

arrhythmias Tachycardia

Palpitations

VascularDisorders

Unspecific

vascular

symptoms Oedema

Vasodilatation Hypotension

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Indialysispatientswithmalignanthypertensionandhypovolaemiaadistinctfallinbloodpressurecanoccurasaresult

ofvasodilation.

4.9Overdose

Symptoms

Thefollowingsymptomsareobservedincasesofseverenifedipineintoxication:

Disturbancesofconsciousnesstothepointofcoma,adropinbloodpressure,tachycardiac/bradycardiacheartrhythm

disturbances,hyperglycaemia,metabolicacidosis,hypoxia,cardiogenicshockwithpulmonaryoedema.

Treatment

Asfarastreatmentisconcerned,eliminationoftheactivesubstanceandtherestorationofstablecardiovascular

conditionshavepriority.

Afteroralingestion,thoroughgastriclavageisindicated,ifnecessaryincombinationwithirrigationofthesmall

intestine.

Particularlyincasesofintoxicationwithslow-releaseproductslikeAdalatLA,eliminationmustbeascompleteas

possible,includingthesmallintestine,topreventtheotherwiseinevitablesubsequentabsorptionoftheactive

RespiratoryDisorders

Upperrespiratory

tractsymptoms Nosebleed

Nasalcongestion Dyspnoea

GastrointestinalDisorders

Gastro-intestinal

symptoms Constipation Gastrointestinal and

abdominalpain

Nausea

Dyspepsia

Flatulence

Drymouth Gingival

hyperplasia Bezoar

Dysphagia

Intestinal

obstruction

Intestinalulcer

Vomiting

HepatobiliaryDisorders

Mildtomoderate

hepaticreactions Transientincreasein

liverenzymes

SkinandSubcutaneousTissueDisorders

Unspecificskin

reactions Erythema

MusculoskeletalandConnectiveTissueDisorders

Unspecific

jointandmuscular

disorders Musclecramps

Jointswelling

RenalandUrinaryDisorders

Urinarydisorders Polyuria

Dysuria

ReproductiveSystemDisorders

Sexual

dysfunction Erectiledysfunction

GeneralDisordersandAdministrationSiteConditions

Generalfeelingof

illness Feelingunwell Unspecificpain

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Haemodialysisservesnopurpose,asnifedipineisnotdialysable,butplasmapheresisisadvisable(highplasmaprotein

binding,relativelylowvolumeofdistribution).

Hypotensionasaresultofcardiogenicshockandarterialvasodilatationcanbetreatedwithcalcium(10-20mlofa10

%calciumgluconatesolutionadministeredslowlyI.V.andrepeatedifnecessary).Asaresulttheserumcalciumcan

reachtheuppernormalrangetoslightlyelevatedlevels.Ifaninsufficientincreaseinbloodpressureisachievedwith

calcium,vasoconstrictingsympathomimeticssuchasdopamineornoradrenalineshouldbeadministered.Thedosage

ofthesedrugsshouldbedeterminedsolelybythepatient'sresponse.

Symptomaticbradycardiamaybetreatedwithbeta-sympathomimetics,andinlife-threateningbradycardiac

disturbancesofheartrhythm,temporarycardiacpacemakertherapycanbeadvisable.

Additionalliquidorvolumemustbeadministeredwithcautionbecauseofthedangerofoverloadingtheheart.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:C08CA05

Nifedipineisacalciumantagonistofthe1,4-dihydropyridinetype.Calciumantagonistsreducethetransmembranal

influxofcalciumionsthroughtheslowcalciumchannelintothecell.Asaspecificandpotentcalciumantagonist

nifedipineactsparticularlyonthecellsofthemyocardiumandthesmoothmusclecellsofthecoronaryarteriesandthe

peripheralresistancevessels.Themainactionofnifedipineistorelaxarterialsmoothmuscle,bothinthecoronaryand

peripheralcirculation.TheAdalatLAtabletisformulatedtoachievecontrolleddeliveryofnifedipineinarelease

profilesufficienttoenableonce-dailyadministrationtobeeffectiveinclinicaluse.

Inhypertension,themainactionofnifedipineistocauseperipheralvasodilatationandthusreduceperipheral

resistance.Nifedipineadministeredonce-dailyprovides24-hourcontrolofraisedbloodpressure.Nifedipinecauses

reductioninbloodpressuresuchthatthepercentageloweringisproportionaltoitsinitiallevel.Innormotensive

individuals,nifedipinehaslittleornoeffectonbloodpressure.

Inangina,AdalatLAreducesperipheralandcoronaryvascularresistance,leadingtoanincreaseincoronaryblood

flow,cardiacoutputandstrokevolume,whilstdecreasingafter-load.Additionally,nifedipinedilatessubmaximally

bothclearandatheroscleroticcoronaryarteries,thusprotectingtheheartagainstcoronaryarteryspasmandimproving

perfusiontotheischaemicmyocardium.NifedipinereducesthefrequencyofpainfulattacksandtheischaemicECG

changesirrespectiveoftherelativecontributionfromcoronaryarteryspasmoratherosclerosis.

Inamulti-national,randomised,double-blind,prospectivestudyinvolving6321hypertensivepatientswithatleastone

additionalriskfactorfollowedover3to4.8years,AdalatLA30and60(nifedipineGITS)wereshowntoreduce

cardiovascularandcerebrovasculareventstoacomparabledegreeasastandarddiureticcombination.

Inthemulticentre,randomized,placebo-controlled,double-blindACTIONtrialwithafollow-upof5yearsinvolving

7665patientswithstableanginapectorisonbestpracticestandardtreatment.Theeffectsonclinicaloutcomesof

nifedipineLAvsplacebowereinvestigated.

Theprimaryendpointforefficacy(combinedrateofdeathfromanycause,acutemyocardialinfarction,refractory

angina,newovertheartfailure,debilitatingstroke,andperipheralrevascularization)didnotdifferbetweenpatients

assignednifedipineLA(n=3825)andpatientsallocatedplacebo(n=3840)(P=0.54).

Inapredefinedsubgroupanalysiswhichincluded3997anginapatientswithhypertensionatbaselinenifedipineLAled

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NifedipineLAhasbeendemonstratedtobesafeastheprimaryendpointforsafety(combinedrateofdeathfromany

cause,acutemyocardialinfraction,anddebilitatingstroke)wassimilarinbothtreatmentgroups(P=0.86).

NifedipineLAhadapositiveeffectontwoofthethreepredefinedsecondaryendpoints.Thecombinedrateofdeath,

majorcardiovascularevents,revascularization,andcoronaryangiography(CAG)wasreducedby11%(P=0.0012),the

mainreasonbeingthepronouncedreductionintheneedforcoronaryangiography.Therewere150fewerCAGsasthe

firsteventinthenifedipinegroupwhencomparedtoplacebo.Anyvasculareventwasreducedby9%(P=0.027),the

mainreasonbeingthereducedneedforpercutaneouscoronaryinterventionsandbypasssurgery.Intotal,therewere89

fewerproceduresasfirsteventsinthenifedipinegroupcomparedtoplacebo.Theoutcomeofthethirdsecondary

endpoint'majorcardiovascularevent'didnotshowdifferencesbetweenthetwotreatmentgroups(P=0.26).

5.2Pharmacokineticproperties

Generalcharacteristics:

AdalatLAtabletsareformulatedtoprovidenifedipineatanapproximatelyconstantrateover24hours.Nifedipineis

releasedfromthetabletatazero-orderratebyamembrance-controlled,osmoticpush-pullprocess.The

pharmacokineticprofileofthisformulationischaracterizedbylowpeak-troughfluctuation.0-24hourplasma

concentrationversustimeprofilesatsteady-stateareplateau-like,renderingtheAdalatLAtabletappropriateforonce-

a-dayadministration.

ThedeliveryrateisindependentofgastrointestinalpHormotility.Uponswallowing,thebiologicallyinertcomponents

ofthetabletremainintactduringgastrointestinaltransitandareeliminatedinthefaecesasaninsolubleshell.

Orallyadministerednifedipineisalmostcompletelyabsorbedinthegastro-intestinaltract.Thesystemicavailability

oforallyadministerednifedipineimmediatereleaseformulations(nifedipinecapsules)is45-56%owingtoafirstpass

effect. Atsteady-state,thebioavailabilityofAdalatLAtabletsrangesfrom68-86%relativetoAdalatcapsules.

Administrationinthepresenceoffoodslightlyalterstheearlyrateofabsorptionbutdoesnotinfluencetheextentof

drugavailability.

Nifedipineisabout95%boundtoplasmaprotein(albumin).Thedistributionhalf-lifeafterintravenousadministration

hasbeendeterminedtobe5to6minutes.

Afteroraladministrationnifedipineismetabolisedinthegutwallandintheliverprimarilybyoxidativeprocesses.

Thesemetabolitesshownopharmacodynamicactivity.Nifedipineiseliminatedintheformofitsmetabolites,

predominantlyviathekidneys,withapproximately5-15%beingexcretedviathebileinthefaeces.Non-metabolised

nifedipinecanbedetectedonlyintraces(below1.0%)intheurine.

Theterminaleliminationhalf-lifeis1.7to3.4hinconventionalformulations(nifedipinecapsules).Theterminalhalf-

lifefollowingAdalatLAadministrationdoesnotrepresentameaningfulparameterasaplateau-likeplasma

concentrationismaintainedduringreleasefromthetabletsandabsorption.

Characteristicsinpatients:

Therearenosignificantdifferencesinthepharmacokineticsofnifedipinebetweenhealthysubjectsandsubjectswith

renalimpairment.Therefore,dosageadjustmentisnotneededinthesepatients.

Inpatientswithhepaticimpairment,theeliminationhalf-lifeisdistinctlyprolongedandthetotalclearanceisreduced.

Owingtothedurationofactionoftheformulation,AdalatLAshouldnotbeadministeredinthesepatients.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsingleandrepeateddosetoxicity,

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Followingacuteoralandintravenousadministrationofnifedipineinvariousanimalspecies,thefollowingLD

(mg/kg)valueswereobtained:

Insubacuteandsubchronictoxicitystudiesinratsanddogs,nifedipinewastoleratedwithoutdamageatdosesofupto

50mg/kg(rats)and100mg/kg(dogs)p.o.overperiodsofthirteenandfourweeks,respectively.Following

intravenousadministration,dogstoleratedupto0.1mg/kgnifedipineforsixdayswithoutdamage.Ratstolerateddaily

intravenousadministrationof2.5mg/kgnifedipineoveraperiodofthreeweekswithoutdamage.

Inchronictoxicitystudiesindogswithtreatmentlastinguptooneyear,nifedipinewastoleratedwithoutdamageat

dosesuptoandincluding100mg/kgp.o.Inrats,toxiceffectsoccurredatconcentrationsabove100ppminthefeed

(approximately5-7mg/kgbodyweight).

Inacarcinogenicitystudyinrats(twoyears),therewasnoevidenceofacarcinogeniceffectofnifedipine.

Nifedipinehasbeenshowntoproduceteratogenicfindingsinrats,miceand rabbits,includingdigitalanomalies,

malformationoftheextremities,cleftpalatecleftsternum,andmalformationoftheribs.Digitalanomalies

andmalformationoftheextremitiesarepossiblyaresultofcompromiseduterinebloodflow,buthavealsobeen

observedinanimalstreatedwithnifedipinesolelyaftertheendoftheorganogenesisperiod.

Nifedipineadministrationwasassociatedwithavarietyofembryotoxic,placentotoxicandfetotoxiceffects,including

stuntedfetuses(rats,mice,rabbits),smallplacentasandunderdevelopedchorionicvilli(monkeys),embryonicandfetal

deaths(rats,mice,rabbits)andprolongedpregnancy/decreasedneonatalsurvival(rats;notevaluatedinotherspecies).

Allofthedosesassociatedwiththeteratogenic,embryotoxicorfetotoxiceffectsinanimalswerematernallytoxicand

severaltimestherecommendedmaximumdoseforhumans.

Ininvitroandinvivotests,nifedipinehasnotbeenassociatedwithmutagenicproperties.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore

Polyethyleneoxide

Hypromellose

MagnesiumStearate

Sodiumchloride

Ferricoxide,red(E172)

TabletCoating

Hypromellose

Ferricoxide,red(E172)

Celluloseacetate

Macrogol

Hydroxypropylcellulose

Titaniumdioxide(E171)

Propyleneglycol

Mouse: Oral:494(421-572)*; i.v.:4.2(3.8-4.6)*.

Rat: Oral:1022(950-1087)*; i.v.:15.5(13.7-17.5)*.

Rabbit: Oral:250-500; i.v.:2-3.

Cat: Oral:~100; i.v.:0.5-8.

Dog: Oral:>250; i.v.:2-3.

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6.2Incompatibilities

Notapplicable.

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductisthedateshownontheblisterstripsandoutercartonoftheproductasmarketedinthe

countryoforigin.

6.4Specialprecautionsforstorage

Storeintheoriginalcontainer.Thetabletsshouldbeprotectedfromstronglight.Donotstoreabove30 °

6.5Natureandcontentsofcontainer

Re-packagedcardboardcartoncontainingfourblisterstrips(7tabletsperstrip).

Packsize:28

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

ProfindWholesaleLtd

Unit625,KilshaneAvenue

NorthwestBusinessPark

Dublin15

Ireland

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1500/037/002

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:8 th

January2010

10DATEOFREVISIONOFTHETEXT

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