ADALAT LA

Main information

  • Trade name:
  • ADALAT LA
  • Dosage:
  • 60 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:
  • PPA1473/005/002
  • Authorization date:
  • 09-01-2009
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PPA1473/005/002

CaseNo:2050891

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

McDowellPharmaceuticals

4AltonaRoad,Lisburn,N.Ireland,BT275QB

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

AdalatLA60mgProlonged-ReleaseTablet

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom09/01/2009.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

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PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AdalatLA60mgProlongedReleaseTablet.

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains60mgnifedipine.

Excipients:Sodium

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

ProductimportedfromtheUK

Prolongedreleasefilm-coatedtablet.

Pink,circularconvextabletswith‘Adalat60’markedononeside.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthetreatmentofallgradesofhypertension.

Forthemanagementofchronicstableanginapectoriseitherasmonotherapyorincombinationwithabeta-blocker.

4.2Posologyandmethodofadministration

Posology

Fororaladministration,thetabletsshouldbeswallowedwholewithaglassofwater,independentlyofmeals.The

tabletsshouldbetakenatapproximately24-hourintervals,i.e.atthesametimeeachday,preferablyduringthe

morning.AdalatLAtabletsmustbeswallowedwhole;undernocircumstancesshouldtheybebitten,chewedorbroken

Inmildtomoderatehypertension,therecommendedinitialdoseisone20mgtabletonce-daily.Inseverehypertension,

therecommendedinitialdoseisone30mgtabletonce-daily.Ifnecessary,thedosagecanbeincreasedaccordingto

individualrequirementsuptoamaximumof90mgonce-daily.

Forthemanagementofanginapectoris,therecommendedinitialdoseisone30mgtabletonce-daily.Thedosagecan

beincreasedaccordingtoindividualrequirementsuptoamaximumof90mgonce-daily.

PatientsinwhomhypertensionoranginalsymptomsarecontrolledonAdalatcapsulesorAdalatRetardmaybesafely

switchedtoAdalatLA.Prophylacticanti-anginalefficacyismaintainedwhenpatientsareswitchedfromothercalcium

antagonistssuchasdiltiazemorverapamiltoAdalatLA.Patientsswitchedfromothercalciumantagonistsshould

initiatetherapyattherecommendedinitialdoseof30mgAdalatLAonce-daily.Subsequenttitrationtoahigherdose

maybeinitiatedaswarrantedclinically.

Thepharmacokineticsofnifedipinearealteredintheelderlysothatlowermaintenancedosesofnifedipinemaybe

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Co-adminstrationwithCYP3A4inhibtiorsorCYP3A4inducersmayresultintherecommendationtoadaptthe

nifedipinedoseornottousenifedipineatall(seesection4.5)

Patientswithrenalimpairmentshouldnotrequireadjustmentofdosage.

Treatmentmaybecontinuedindefinitely.

Nifedipineisnotrecommendedforuseinchildren.AdalatLAshouldnotbetakenwithgrapefruitjuice(seeSection

4.5).

4.3Contraindications

-AdalatLAshouldnotbeadministeredtopatientswithknownhypersensitivitytonifedipineorotherdihydropyridines

becauseofthetheoreticalriskofcross-reactivity.

-AdalatLAshouldnotbeadministeredtowomencapableofchild-bearingortonursingmothers.

-AdalatLAshouldnotbeusedincardiogenicshock,clinicallysignificantaorticstenosis,unstableanginapectoris,or

duringorwithinonemonthofamyocardialinfarction.

-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-blockingdrugsandotherantihypertensiveagents,butthepossibility

ofanadditiveeffectresultinginposturalhypotensionshouldbeborneinmind.AdalatLAwillnotpreventpossible

reboundeffectsaftercessationofotherantihypertensivetherapy.

AdalatLAshouldbeusedwithcautioninpatientswhosecardiacreserveispoor.Deteriorationofheartfailurehas

occasionallybeenobservedwithnifedipine.

Ischaemicpainhasbeenreportedinasmallproportionofpatientsfollowingtheintroductionofnifedipinetherapy.

Althougha'steal'effecthasnotbeendemonstrated,patientsexperiencingthiseffectshoulddiscontinuenifedipine

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DiabeticpatientstakingAdalatLAmayrequireadjustmentoftheircontrol.

Indialysispatientswithmalignanthypertensionandhypovolaemia,amarkeddecreaseinbloodpressurecanoccur.

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(afteroral

administration)ortheclearanceofnifedipine.

Theextentaswellasthedurationofinteractionsshouldbetakenintoaccountwhenadministeringnifedipinetogether

withthefollowingdrugs:

Rifampicin:RifampicinstronglyinducesthecytochromeP4503A4system.Uponco-administrationwithrifampicicn,

thebioavailabilityofnifedipineisdistinctlyreducedandthusitsefficacyweakened.Theuseofnifedipinein

combinationwithrifampicinisthereforecontraindicated(seesection4.3).

Uponco-administrationofweaktomoderateinhibitorsofthecyctochromeP4503A4system(listedimmediately

below),thebloodpressureshouldbemonitoredand,ifnecessary,areductioninthenifedipinedoseconsidered(see

Sections4.2and4.4).Inthemajorityofthesecasesnoformalstudiestoassessthepotentialforadruginteraction

betweennifedipineandthedrug(s)listedhavebeenundertaken,thusfar.

Macrolideantibiotics(e.g.,erythromycin):CertainmacrolideantibioticsareknowntoinhibitthecyctochromeP450

3A4mediatedmetabolismofotherdrugs.Thereforethepotentialforanincreaseofnifedipineplasmaconcentrations

uponco-administrationofbothdrugscannotbeexcluded(seeSection4.4).

Azithromycin,althoughstructurallyrelatedtotheclassofmacrolideantibioticsisvoidofCYP3A4inhibition.

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

P4503A4mediatedmetabolismofnifedipine.Whenadministeredtogetherwithnifedipine,asubstantialincreasein

plasmaconcentrationsofnifedipineduetoadecreasedfirstpassmetabolismandadecreasedeliminationcannotbe

excluded(seeSection4.4).

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

Whenadministeredorallytogetherwithnifedipine,asusbstantialincreaseinsystemicbioavailabilityofnifedipinedue

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Fluoxetine:FluoxetinehasbeenshowntoinhibitinvitrothecytochromeP4503A4mediatedmetabolismofnifedipine.

Thereforeanincreaseofnifedipineplasmaconcentrationsuponco-administrationofbothdrugscannotbeexcluded

(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:DuetoitsinhibitonofcytochromeP4503A4,cimetidineelevatestheplasmaconcentrationsofnifedipine

andmaypotentiatetheantihypertensiveeffect(seeSection4.4).

Diltiazem:Diltiazemdecreasestheclearanceofnifedipineand,hence,increasesplasmanifedpinelevels.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.Asbothdrugshavebeenshowntoreducetheplasmaconcentrationsofthestructurallysimilar

calciumchannelblocker,nimodipine,duetoenzymeinduction,adecreaseinnifedipineplasmaconcentrationsand

henceadecreaseinefficacycannotbeexcluded.

Effectsofnifedipineonotherdrugs

Nifedipinemayincreasethebloodpressureloweringeffectofconcomitantappliedantihypertensives,suchas:

-diuretics

-beta-blockers

-Ace-inhibitors

-AT-1antagonists

-othercalciumantagonists

-alpha-adrenergicblockingagents

-PDE5inhibitors

-alpha-methyldopa

Whennifedipineisadministeredsimultaneouslywithbeta-receptorblockersthepatientshouldbecarefullymonitored,

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Digoxin:Thesimultaneousadministrationofnifedipineanddigoxinmayleadtoreduceddigoxinclearanceand,hence,

anincreaseintheplasmadigoxinlevel.Thepatientshouldthereforebecheckedforsymptomsofdigoxinoverdosage

asaprecautionand,ifnecessary,theglycosidedoseshouldbereducedtakingaccountoftheplasmaconcentrationof

digoxin.

Quinidine:Whennifedipineandquinidinehavebeenadministeredsimultaneously,loweredquinidinelevels,orafter

discontinuationofnifedipine,adistinctincreaseinplasmaconcentrationsofquinidine,havebeenobservedin

individualcases.Forthisreason,whennifedipineiseitheradditionallyadministeredordiscontinued,monitoringofthe

quinidineplasmaconcentration,andifnecessary,adjustmentofthequinidinedosearerecommended.Someauthors

reportedincreasedplasmaconcentrationsofnifedipineuponco-administrationofbothdrugs,whileothersdidnot

observeanalterationinthepharmacokineticsofnifedipine.

Thereforethebloodpressureshouldbecarefullymonitored,ifquinidineisaddedtoanexistingtherapywithnifedipine.

Ifnecessary,thedoseofnifedipineshouldbedecreased.

Tacrolimus:TacrolimushasbeenshowntobemetabolisedviathecyctochromeP4503A4system.Datarecently

publishedindicatethatthedoseoftacrolimusadministeredsimultaneouslywithnifedipinemaybereducedin

individualcases.Uponco-administrationofbothdrugs,thetacrolimusplasmaconcentrationsshouldbemonitoredand,

ifnecessary,areductioninthetacrolimusdoseconsidered.

Drugfoodinteractions

GrapefruitjuiceinhibitsthecytochromeP4503A4system.Administrationofnifedipinetogetherwithgrapefruitjuice

thusresultsinelevatedplasmaconcentrationsandprolongedactionofnifedipineduetoadecreasedfirstpass

metabolismorreducedclearance.Asaconsequence,thebloodpressureloweringeffectofnifedipinemaybeincreased.

Afterregularintakeofgrapefruitjuice,thiseffectmaylastforatleastthreedaysafterthelastingestionofgrapefruit

juice.

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

Pregnancy

AdalatLAiscontra-indicatedinwomencapableofchildbearing.

ThesafetyofAdalatLAforuseinhumanpregnancyhasnotbeenestablished.Evaluationofexperimentalanimal

studieshasshownreproductivetoxicityconsistingofembryotoxicityandteratogeniceffectsatmaternallytoxicdoses.

Lactation

AdalatLAiscontra-indicatedinnursingmothersasnifedipinemaybepresentinbreastmilk.

Insinglecasesofinvitrofertilisationcalciumantagonistslikenifedipinehavebeenassociatedwithreversible

biochemicalchangesinthespermatozoa'sheadsectionthatmayresultinimpairedspermfunction.Inthosemenwho

arerepeatedlyunsuccessfulinfatheringachildbyinvitrofertilisation,andwherenootherexplanationcanbefound,

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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

ImmuneSystemDisorder

PsychiatricDisorders

Clinical

Description Common

1%to

<10% Uncommon>0.1%

To<1% Rare>0.01%to

<0.1% VeryRare

<0.01%

Acute

hypersensitivity

reactions Allergicreaction

Allergicoedema/

Angioedama Pruritus

Urticaria

Rash Anaphylactic/

anaphylactoid

reaction

Behavioural

disturbancesand

sleepdisorders Anxietyreactions

Sleepdisorders

Unspecific

cerebrovascular

symptoms Headache Vertigo

Migraine

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EyeDisorders

CardiacDisorders

VascularDisorders

RespiratoryDisorders

neurological

symptoms Tremor

Unspecific

altered

peripheral

perception Par/

dysaesthesia

Unspecificeye

disorders Visual

disturbances

Unspecific

arrhythmias Tachycardia

Palpitations

Unspecific

vascular

symptoms Oedema

Vasodilation Hypotension

Syncope

Upper

respiratorytract

symptoms Nosebleed

Nasalcongestion Dyspnoea

Gastro-intestinal

symptoms Constipation Gastrointestinal

andabdominal

pain

Nausea Gingival

Hyperplasia Bezoar

Dysphagia

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HepatobiliaryDisorders

SkinandSubcutaneousTissueDisorders

MusculoskeletalandConnectiveTissueDisorders

RenalandUrinaryDisorders

ReproductiveSystemDisorders

GeneralDisordersandAdministrationSiteConditions

Indialysispatientswithmalignanthypertensionandhypovolaemiaadistinctfallinbloodpressurecanoccurasaresult

Dyspepsia

Flatulence

Drymouth obstruction

Intestinalulcer

Vomiting

Mildtomoderate

hepaticreactions Transient

increaseinliver

enzymes

Unspecificskin

reactions Erythema

Unspecificjoint

andmuscular

disorders Musclecramps

Jointswelling

Urinary

Disorders Polyuria

Dysuria

Sexual

Dysfunction Erectile

dysfuction

Generalfeelingof

illness Feelingunwell Unspecificpain

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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

substance.

Haemodialysisservesnopurpose,asnifedipineisnotdialysable,butplasmapheresisisadvisable(highplasmaprotein

binding,relativelylowvolumeofdistribution).

Hypotensionasaresultofcardiogenicshockandarterialvasodilatationcanbetreatedwithcalcium(10-20mlofa10

%calciumgluconatesolutionadministeredslowlyI.V.andrepeatedifnecessary).Asaresulttheserumcalciumcan

reachtheuppernormalrangetoslightlyelevatedlevels.Ifaninsufficientincreaseinbloodpressureisachievedwith

calcium,vasoconstrictingsympathomimeticssuchasdopamineornoradrenalineshouldbeadministered.Thedosageof

thesedrugsshouldbedeterminedsolelybythepatient'sresponse.

Symptomaticbradycardiamaybetreatedwithbeta-sympathomimetics,andinlifethreateningbradycardiac

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

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Inangina,AdalatLAreducesperipheralandcoronaryvascularresistance,leadingtoanincreaseincoronaryblood

flow,cardiacoutputandstrokevolume,whilstdecreasingafter-load.Additionally,nifedipinedilatessubmaximally

bothclearandatheroscleroticcoronaryarteries,thusprotectingtheheartagainstcoronaryarteryspasmandimproving

perfusiontotheischaemicmyocardium.NifedipinereducesthefrequencyofpainfulattacksandtheischaemicECG

changesirrespectiveoftherelativecontributionfromcoronaryarteryspasmoratherosclerosis.

Inmulti-national,randomised,double-blind,prospectivestudyinvolving6321hypertensivepatientswithatleastone

additionalriskfactorfollowedover3to4.8years,AdalatLA30and60(nifedipineGITS)wereshowntoreduce

cardiovascularandcerebrovasculareventstoacomparabledegreeasastandarddiureticcombination.

Inthemulticentre,randomised,placebo-controlled,double-blindACTIONtrialwithafollowupof5yearsinvolving

7665patientswithstableanginapectorisonbestpracticestandardtreatment.

TheeffectsonclinicaloutcomesofnifedipineLAvsplacebowereinvestigated.Theprimaryendpointforefficacy

(combinedrateofdeathfromanycause,acutemyocardialinfarction,refractoryangina,newovertheartfailure,

debilitatingstroke,andperipheralrevascularization)didnotdifferbetweenpatientsassignednifedipineLA(n=3825)

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

Inapredefinedsubgroupanalysiswhichincluded3997anginapatientswithhypertensionatbaselinenifedipineLAled

toasignificant13%reductionoftheprimaryendpointforefficacy.

NifedipineLAhasbeendemonstratedtobesafeastheprimaryendpointforsafety(combinedrateofdeathfromany

cause,acutemyocardialinfarction,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-orderratebyamembrane-controlled,osmoticpush-pullprocess.Thepharmacokinetic

profileofthisformulationischaracterisedbylowpeak-troughfluctuation.

0-24hourplasmaconcentrationversustimeprofilesatsteady-stateareplateau-like,renderingtheAdalatLAtablet

appropriateforonce-a-dayadministration.

ThedeliveryrateisindependentofgastrointestinalpHormotility.Uponswallowing,thebiologicallyinertcomponents

ofthetabletremainintactduringgastrointestinaltransitandareeliminatedinthefaecesasaninsolubleshell.

Orallyadministerednifedipineisalmostcompletelyabsorbedinthegastro-intestinaltract.Thesystemicavailabilityof

orallyadministerednifedipineimmediatereleaseformulations(nifedipinecapsules)is45-56%owingtoafirstpass

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

Administrationinthepresenceoffoodslightlyalterstheearlyrateofabsorption,butdoesnotinfluencetheextentof

drugavailability.

Nifedipineisabout95%boundtoplasmaprotein(albumin).Thedistributionhalflifeafterintravenousadministration

hasbeendeterminedtobe5to6minutes.

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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,

genotoxitictyandcarcinogenicpotential.

Followingacuteoralandintravenousadministrationofnifedipineinvariousanimalspecies,thefollowingLD50

(mg/kg)valueswereobtained:

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.

*95%confidenceinterval.

Insubacuteandsubchronictoxicitystudiesinratsanddogs,nifedipinewastoleratedwithoutdamageatdosesofupto

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

administration,dogstoleratedupto0.1mg/kgnifedipineforsixdayswithoutdamage.Ratstolerateddailyintravenous

administrationof2.5mg/kgnifedipineoveraperiodofthreeweekswithoutdamage.

Inchronictoxicitystudiesindogswithtreatmentlastinguptooneyear,nifedipinewastoleratedwithoutdamageat

dosesuptoandincluding100mg/kgp.o.Inrats,toxiceffectsoccurredatconcentrationsabove100ppminthefeed

(approximately5-7mg/kgbodyweight).

Inacarcinogenicitystudyinrats(twoyears),therewasnoevidenceofacarcinogeniceffectofnifedipine.

Nifedipinehasbeenshowntoproduceteratogenicfindingsinrats,miceandrabbits,includingdigitalanomalies,

malformationoftheextremities,cleftpalates,cleftsternum,andmalformationoftheribs.

Digitalanomaliesandmalformationoftheextremitiesarepossiblyaresultofcompromiseduterinebloodflow,but

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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

OsmoticLayer:

Polyethyleneoxide

Sodiumchloride

Hypromellose

Redferricoxide(E172)

Magnesiumstearate

MembraneCoating:

Celluloseacetate

Macrogol4000

Overcoating:

Hydroxypropylcellulose

Hypromellose

Propyleneglycol

Titaniumdioxide(E172)

Ironoxide,red(E172)

Polish:

Hypromellose

PrintingInk:

BlackinkOpacodeS-1-8106,(contains:Ironoxide,black(E172)andShellac)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Theshelf-lifeexpirydateofthisproductshallbethedateshownonthecontainerandouterpackageoftheproducton

themarketinthecountryoforigin.

6.4Specialprecautionsforstorage

Storeinoriginalcontainer.

Thetabletsshouldbeprotectedfromstronglight.

Donotstoreabove30 º

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6.5Natureandcontentsofcontainer

BlisterpackscomposedofPPbackedwithaluminiumfoil,containing28tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7ParallelProductAuthorisationHolder

McDowellPharmaceuticals

4AltonaRoad,

Lisburn,

N.IrelandBT275QB

8ParallelProductAuthorisationNumber

PPA1473/5/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

DateofFirstAuthorisation:9thJanuary2009

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