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:
  • PPA1659/039/002
  • Authorization date:
  • 02-09-2011
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AdalatLA30mgProlongedReleaseTablet

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onetabletcontains30mgnifedipine.

Excipients:Each30mgtabletalsocontains9.4mgofsodium.

Forafulllistofexcipients,seeSection6.1.

3PHARMACEUTICALFORM

Prolonged-releasetablet.

ProductimportedfromtheUK:

Pink,round,convexprolonged-releasetabletwithalaserholeononesideandmarkedwithAdalat30.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthetreatmentofallgradesofhypertension.

Forthemanagementofchronicstableanginapectoriseitherasmonotherapyorincombinationwithabeta-blocker.

4.2Posologyandmethodofadministration

Methodofadministration

Oraluse

Asfaraspossiblethetreatmentmustbetailoredtotheneedsoftheindividual.

Dependingontheclinicalpictureineachcase,thebasicdosemustbeintroducedgradually.

Unlessotherwiseprescribed,thefollowingdosageguidelinesarerecommendedforadults:

Forcoronaryheartdisease:

Chronicstableanginapectoris(anginaofeffort)

1AdalatLA30mgtabletoncedaily(1x30mg/day)

Forhypertension:

1AdalatLA30mgtabletoncedaily(1x30mg/day)

Ingeneraltherapyshouldbeinitiatedwith30mgoncedaily.

Whereregisteredastartingdoseof20mgoncedailymaybeconsideredwhenmedicallyindicated.Interimdosesi.e.

40mg,50mgetc.canbeappliedbycombinationsofi.e.20mg+20mgor20mg+30mgtablets.

Dependingontheseverityofthediseaseandthepatient'sresponsethedosecanbeincreasedinstagesupto90mgonce

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CoadministrationwithCYP3A4inhibitorsorCYP3A4inducersmayresultintherecommendationtoadaptthe

nifedipinedoseornottousenifedipineatall(see"Interactionwithothermedicinalproductsotherformsof

interaction").

DurationofTreatment

Theattendingdoctorwilldeterminethedurationofuse.

Administration

AsaruleAdalatLAtabletsareswallowedwholewithalittleliquid,irrespectiveofmealtimes. i

Grapefruitjuiceisto

beavoided(seeInteractionwithothermedicinalproductsandotherformsofinteraction).

Additionalinformationonspecialpopulations ii

Childrenandadolescents

ThesafetyandefficacyofAdalatLAinchildrenbelow18yearshasnotbeenestablished.

Geriatricpatients

BasedonpharmacokineticdataforAdalatLAnodoseadaptationinelderlypeopleabove65yearsisnecessary.

Patientswithhepaticimpairment

Inpatientswithimpairedliverfunction,carefulmonitoringand,inseverecases,adosereductionmaybenecessary.

Patientswithrenalimpairment

Basedonpharmacokineticdatanodosageadjustmentisrequiredinpatientswithrenalimpairment(see

“pharmacokinetic”)

Thetabletsmustnotbechewedorbrokenup.

4.3Contraindications

AdalatLAmustnotbeadministeredtopatientswithknownhypersensitivitytonifedipineorotherdihydropyridines

becauseofthetheoreticalriskofcross-reactivity.

AdalatLAmustnotbeadministeredduringpregnancyortonursingmothers.

AdalatLAmustnotbeusedincardiogenicshock,clinicallysignificantaorticstenosis,unstableanginapectoris,or

duringorwithinonemonthofamyocardialinfarction.

AdalatLAmustnotbeusedforthetreatmentofacuteattacksofangina.

ThesafetyofAdalatLAinmalignanthypertensionhasnotbeenestablished.

AdalatLAmustnotbeusedforsecondarypreventionofmyocardialinfarction.

Owingtothedurationofactionoftheformulation,AdalatLAmustnotbeadministeredtopatientswithhepatic

impairment.

AdalatLAmustnotbeadministeredtopatientswithahistoryofgastro-intestinalobstruction,oesophagealobstruction,

oranydegreeofdecreasedlumendiameterofthegastro-intestinaltract.

AdalatLAmustnotbeusedinpatientswithKockpouch(ileostomyafterproctocolectomy)

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AdalatLAmustnotbeadministeredconcomitantlywithrifampicinsinceeffectiveplasmalevelsofnifedipinemaynot

beachievedowingtoenzymeinduction(seeSection4.5).

4.4Specialwarningsandprecautionsforuse

AdalatLAtabletsmustbeswallowedwhole;undernocircumstancesshouldtheybebitten,chewedorbrokenup.

TheoutermembraneoftheAdalatLAtabletisnotdigestedand,therefore,whatappearstobethecompletetabletmay

beseeninthetoiletorassociatedwiththepatient'sstools.

Cautionshouldbeexercisedinpatientswithhypotensionasthereisariskoffurtherreductioninbloodpressure.

AdalatLAmaybeusedincombinationwithbeta-blockingdrugsandotherantihypertensiveagentsbutthepossibility

ofanadditiveeffectresultinginposturalhypotensionshouldbeborneinmind.AdalatLAwillnotpreventpossible

reboundeffectsaftercessationofotherantihypertensivetherapy.

AdalatLAshouldbeusedwithcautioninpatientswhosecardiacreserveispoor.Deteriorationofheartfailurehas

occasionallybeenobservedwithnifedipine.

Ischaemicpainhasbeenreportedinasmallproportionofpatientsfollowingtheintroductionofnifedipinetherapy.

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,bloodpressureshouldbemonitoredand,if

necessary,areductioninthenifedipinedoseconsidered(seeSection4.5).

AstheoutermembraneoftheAdalatLAtabletisnotdigested,careshouldbeexercisedasobstructivesymptomsmay

occur,particularlyinpatientswithpre-existingseveregastrointestinalnarrowing.Bezoarscanoccurinveryrarecases

andmayrequiresurgicalintervention.

AdalatLAmustnotbeadministeredtopatientswithKockpouch(ileostomyafterproctocolectomy).

Afalsepositiveeffectmaybeexperiencedwhenperformingabariumcontrastx-ray.

Patientswithhepaticimpairment

Inpatientswithimpairedliverfunction,carefulmonitoringand,inseverecases,adosereductionmaybenecessary.

Thismedicinalproductcontains9.4mgofsodiumpertablet,thisshouldbetakenintoconsiderationforpatientsona

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4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Drugsthataffectnifedipine

NifedipineismetabolisedviathecytochromeP4503A4system,locatedbothintheintestinalmucosaandintheliver.

Drugsthatareknowntoeitherinhibitortoinducethisenzymesystemmaythereforealterthefirstpass(afteroral

administration)ortheclearanceofnifedipine.

Theextentaswellasthedurationofinteractionsshouldbetakenintoaccountwhenadministeringnifedipinetogether

withthefollowingdrugs:

Rifampicin:

RifampicinstronglyinducesthecytochromeP4503A4system.Uponco-administrationwithrifampicin,the

bioavailabilityofnifedipineisdistinctlyreducedandthusitsefficacyweakened.Theuseofnifedipineincombination

withrifampicinisthereforecontraindicated(seesection4.3).

Uponco-administrationofweaktomoderateinhibitorsofthecytochromeP4503A4system(listedimmediately

below),thebloodpressureshouldbemonitoredand,ifnecessary,areductioninthenifedipinedoseconsidered(see

Sections4.2and4.4).

Inthemajorityofthesecasesnoformalstudiestoassessthepotentialforadruginteractionbetweennifedipineandthe

drugslistedhavebeenundertaken,thusfar.

Macrolideantibiotics(e.g.,erythromycin):

CertainmacrolideantibioticsareknowntoinhibitthecytochromeP4503A4mediatedmetabolismofotherdrugs.

Thereforethepotentialforanincreaseofnifedipineplasmaconcentrationsuponco-administrationofbothdrugscannot

beexcluded(seeSection4.4).

Azithromycin,althoughstructurallyrelatedtotheclassofmacrolideantibioticsisvoidofCYP3A4inhibition.

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

DrugsofthisclasshavebeenshowntoinhibitinvitrothecytochromeP4503A4mediatedmetabolismofnifedipine.

Whenadministeredtogetherwithnifedipine,asubstantialincreaseinplasmaconcentrationsofnifedipineduetoa

decreasedfirstpassmetabolismandadecreasedeliminationcannotbeexcluded(seeSection4.4).

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

DrugsofthisclassareknowntoinhibitthecytochromeP4503A4system.Whenadministeredorallytogetherwith

nifedipine,asubstantialincreaseinsystemicbioavailabilityofnifedipineduetoadecreasedfirstpassmetabolism

cannotbeexcluded(seeSection4.4).

Fluoxetine:

FluoxetinehasbeenshowntoinhibitinvitrothecytochromeP4503A4mediatedmetabolismofnifedipine.Therefore

anincreaseofnifedipineplasmaconcentrationsuponco-administrationofbothdrugscannotbeexcluded(seeSection

4.4).

Nefazodone:

NefazodoneisknowntoinhibitthecytochromeP4503A4mediatedmetabolismofotherdrugs.Thereforeanincrease

innifedipineplasmaconcentrationsuponco-administrationofbothdrugscannotbeexcluded(seeSection4.4).

Quinupristin/dalfopristin:

Simultaneousadministrationofquinupristin/dalfopristinandnifedipine,mayleadtoincreasedplasmaconcentrations

ofnifedipine(seeSection4.4).

Valproicacid:

Asvalproicacidhasbeenshowntoincreasetheplasmaconcentrationsofthestructurallysimilarcalciumchannel

blocker,nimodipine,duetoenzymeinhibition,anincreaseinnifedipineplasmaconcentrationsandhenceanincrease

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Cimetidine:

DuetoitsinhibitionofcytochromeP4503A4,cimetidineelevatestheplasmaconcentrationsofnifedipineandmay

potentiatetheantihypertensiveeffect(seeSection4.4).

Diltiazem:

Diltiazemdecreasestheclearanceofnifedipineand,hence,increasesplasmanifedipinelevels.Therefore,caution

shouldbetakenwhenbothdrugsareusedincombinationandareductionofthenifedipinedosemaybenecessary.

Furtherstudies:

Cisapride:

Simultaneousadministrationofcisaprideandnifedipinemayleadtoincreasedplasmaconcentrationsofnifedipine.

CytochromeP4503A4system-inducinganti-epilepticdrugs,suchasphenytoin,carbamazepineandphenobarbital:

phenytoininducescytochromeP4503A4system.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

-Angiotensin1(AT1)receptor-antagonists,

-othercalciumantagonists

-alpha-adrenergicblockingagents

-PDE5inhibitors

-alpha-methyldopa

Whennifedipineisadministeredsimultaneouslywithbeta-receptorblockersthepatientshouldbecarefullymonitored,

sincedeteriorationofheartfailureisalsoknowntodevelopinisolatedcases.

Digoxin:

Thesimultaneousadministrationofnifedipineanddigoxinmayleadtoreduceddigoxinclearanceand,hence,an

increaseintheplasmadigoxinlevel.Thepatientshouldthereforebecheckedforsymptomsofdigoxinoverdosageasa

precautionand,ifnecessary,theglycosidedoseshouldbereducedtakingaccountoftheplasmaconcentrationof

digoxin.

Quinidine:

Whennifedipineandquinidinehavebeenadministeredsimultaneously,loweredquinidinelevels,orafter

discontinuationofnifedipine,adistinctincreaseinplasmaconcentrationsofquinidine,havebeenobservedin

individualcases.Forthisreason,whennifedipineiseitheradditionallyadministeredordiscontinued,monitoringofthe

quinidineplasmaconcentration,andifnecessary,adjustmentofthequinidinedosearerecommended.Someauthors

reportedincreasedplasmaconcentrationsofnifedipineuponco-administrationofbothdrugs,whileothersdidnot

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Thereforethebloodpressureshouldbecarefullymonitored,ifquinidineisaddedtoanexistingtherapywithnifedipine.

Ifnecessary,thedoseofnifedipineshouldbedecreased.

Tacrolimus:

TacrolimushasbeenshowntobemetabolisedviathecytochromeP4503A4system.Datarecentlypublishedindicate

thatthedoseoftacrolimusadministeredsimultaneouslywithnifedipinemaybereducedinindividualcases.Uponco-

administrationofbothdrugs,thetacrolimusplasmaconcentrationsshouldbemonitoredand,ifnecessary,areduction

inthetacrolimusdoseconsidered.

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.

4.6Fertility,pregnancyandlactation

Pregnancy

AdalatLAiscontra-indicatedduringpregnancy.

AdalatLAshouldnotbeusedbywomenwhointendtogetpregnantinthenearfuture.

ThesafetyofAdalatLAforuseinhumanpregnancyhasnotbeenestablished.Evaluationofexperimentalanimal

studieshasshownreproductivetoxicityconsistingofembryotoxicityandteratogeniceffectsatmaternallytoxicdoses.

Lactation

AdalatLAiscontra-indicatedinbreastfeeding.Nifedipinepassesintothebreastmilk.Asthereisnoexperienceof

possibleeffectsoninfants,breastfeedingshouldfirstbestoppedifnifedipinetreatmentbecomesnecessaryduringthe

breastfeedingperiod.

In-vitrofertalisation

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%).

ThefrequenciesofADRsreportedwithnifedipinecontainingproductsaresummarisedinthetablebelow.

Withineachfrequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.Frequenciesare

definedascommon(1/100to<1/10),uncommon(1/1,000to<1/100)andrare(1/10,000to<1/1,000).

TheADRsidentifiedonlyduringtheongoingpostmarketingsurveillance,andforwhichafrequencycouldnotbe

estimated,arelistedunder“Notknown”.

SystemOrgan

Class

(MedDRA) Common Uncommon Rare Notknown

Bloodand

lymphaticsystem

disorders Agranulocytosis

Leukopenia

Immunesystem

disorders Allergicreaction

Allergicoedema/

angioedema(incl.

larynxoedema 1

Pruritus

Urticaria

Rash Anaphylactic/

anaphylactoid

reaction

Psychiatric

disorders Anxietyreactions

Sleepdisorders

Metabolismand

nutritiondisorders Hyperglycaemia

Nervoussystem

disorders Headache Vertigo

Migraine

Dizziness

Tremor Par-/

Dysaesthesia Hypoaesthesia

Somnolence

Eyedisorders Visualdisturbances Eyepain

Cardiacdisorders Tachycardia

Palpitations Chestpain

(AnginaPectoris)

Vascular

disorder Oedema

Vasodilatation Hypotension

Syncope

Respiratory,

thoracic,and

mediastinal

disorders Nosebleed

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=mayresultinlife-threateningoutcome.

Indialysispatientswithmalignanthypertensionandhypovolaemiaadistinctfallinbloodpressurecanoccurasaresult

ofvasodilation.

4.9Overdose

Symptoms

Thefollowingsymptomsareobservedincasesofseverenifedipineintoxication:

Disturbancesofconsciousnesstothepointofcoma,adropinbloodpressure,tachycardiac/bradycardiacheartrhythm

disturbances,hyperglycaemia,metabolicacidosis,hypoxia,cardiogenicshockwithpulmonaryoedema.

ManagementofOverdose

Asfarastreatmentisconcerned,eliminationoftheactivesubstanceandtherestorationofstablecardiovascular

conditionshavepriority.

Afteroralingestion,thoroughgastriclavageisindicated,ifnecessaryincombinationwithirrigationofthesmall

intestine.

Particularlyincasesofintoxicationwithslow-releaseproductslikeAdalatLA,eliminationmustbeascompleteas

possible,includingthesmallintestine,topreventtheotherwiseinevitablesubsequentabsorptionoftheactive

Gastrointestinal

disorders Constipation Gastrointestinaland

abdominalpain

Nausea

Dyspepsia

Flatulence

Drymouth Gingival

hyperplasia Bezoar

Dysphagia

Intestinal

obstruction

Intestinalulcer

Vomiting

Gastrooesophageal

sphincter

insufficiency

Hepatobiliary

disorders Transientincreasein

liverenzymes Jaundice

Skinand

subcutaneous

tissuedisorders Erythema ToxicEpidermal

Necrolysis

Photosensitivity

allergicreaction

Palpablepurpura

Musculoskeletal

andconnective

tissuedisorders Musclecramps

Jointswelling Arthralgia

Myalgia

Renalandurinary

disorders Polyuria

Dysuria

Reproductive

systemandbreast

disorders Erectiledysfunction

Generaldisorders

and

administrationsite

conditions FeelingunwellUnspecificpain

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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.Asaspecificandpotentcalcium

antagonist,nifedipineactsparticularlyonthecellsofthemyocardiumandthesmoothmusclecellsofthecoronary

arteriesandtheperipheralresistancevessels.

Themainactionofnifedipineistorelaxarterialsmoothmuscle,bothinthecoronaryandperipheralcirculation.The

AdalatLAtabletisformulatedtoachievecontrolleddeliveryofnifedipineinareleaseprofilesufficienttoenableonce-

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

7665patientswithstableanginapectorisonbestpracticestandardtreatmenttheeffectsonclinicaloutcomesof

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,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-orderratebyamembrance-controlled,osmoticpush-pullprocess.The

pharmacokineticprofileofthisformulationischaracterizedbylowpeak-troughfluctuation.0-24hourplasma

concentrationversustimeprofilesatsteady-stateareplateau-like,renderingtheAdalatLAtabletappropriateforonce-

a-dayadministration.

ThedeliveryrateisindependentofgastrointestinalpHormotility.Uponswallowing,thebiologicallyinertcomponents

ofthetabletremainintactduringgastrointestinaltransitandareeliminatedinthefaecesasaninsolubleshell.

Absorption

Orallyadministerednifedipineisalmostcompletelyabsorbedinthegastro-intestinaltract.Thesystemicavailability

oforallyadministerednifedipineimmediatereleaseformulations(nifedipinecapsules)is45-56%owingtoafirstpass

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

Administrationinthepresenceoffoodslightlyalterstheearlyrateofabsorptionbutdoesnotinfluencetheextentof

drugavailability.

Distribution

Nifedipineisabout95%boundtoplasmaprotein(albumin).Thedistributionhalf-lifeafterintravenousadministration

hasbeendeterminedtobe5to6minutes.

Biotransformation

Afteroraladministrationnifedipineismetabolisedinthegutwallandintheliverprimarilybyoxidativeprocesses.

Thesemetabolitesshownopharmacodynamicactivity.Nifedipineiseliminatedintheformofitsmetabolites,

predominantlyviathekidneys,withapproximately5-15%beingexcretedviathebileinthefaeces.Non-metabolised

nifedipinecanbedetectedonlyintraces(below1.0%)intheurine.

Elimination

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

lifefollowingAdalatLAadministrationdoesnotrepresentameaningfulparameterasaplateau-likeplasma

concentrationismaintainedduringreleasefromthetabletsandabsorption.

Characteristicsinpatients:

Therearenosignificantdifferencesinthepharmacokineticsofnifedipinebetweenhealthysubjectsandsubjectswith

renalimpairment.Therefore,dosageadjustmentisnotneededinthesepatients.

Inpatientswithhepaticimpairment,theeliminationhalf-lifeisdistinctlyprolongedandthetotalclearanceisreduced.

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5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsingleandrepeateddosetoxicity,

genotoxicityandcarcinogenicpotential.

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,miceandrabbits,includingdigitalanomalies,

malformationoftheextremities,cleftpalates,cleftsternum,andmalformationoftheribs.

Digitalanomaliesandmalformationoftheextremitiesarepossiblyaresultofcompromiseduterinebloodflow,buthave

alsobeenobservedinanimalstreatedwithnifedipinesolelyaftertheendoftheorganogenesisperiod.

Nifedipineadministrationwasassociatedwithavarietyofembryotoxic,placentotoxicandfetotoxiceffects,including

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

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

ofthedosesassociatedwiththeteratogenic,embryotoxicorfetotoxiceffectsinanimalswerematernallytoxicatseveral

timestherecommendedmaximumdoseforhumans.

Ininvitroandinvivotests,nifedipinehasnotbeenassociatedwithmutagenicproperties.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

TabletCore

Polyethyleneoxide

Hypromellose

Magnesiumstearate

Sodiumchloride

Ferricoxide,red(E172)

Coating

Celluloseacetate

Macrogol(3350)

Hydroxypropylcellulose

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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Propyleneglycol

Titaniumdioxide(E171)

Ferricoxide,red(E172)

PolishandPrint

BlackinkforprintingOpacodeS-1-8106

(Contains:ironoxideblack(E172)andShellac)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelf-lifeexpirydateofthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Storeintheoriginalcontainer.Thetabletsshouldbeprotectedfromstronglight.Donotstoreabove30°C.

6.5Natureandcontentsofcontainer

BlisterpackscomposedofPPbackedwithaluminiumfoil,containing28tablets.Inanover-labelledoutercarton.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

IPSHealthcareLimited

SterlingHouse,

501MiddletonRoad,

Chadderton,

Oldham,

Lancashire,

OL99LY,

UnitedKingdom.

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1659/39/2

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:2 nd

September2011

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