ADALAT RETARD 10 Milligram Tablet Prolonged Release

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
NIFEDIPINE
Available from:
LTT Pharma Limited
INN (International Name):
NIFEDIPINE
Dosage:
10 Milligram
Pharmaceutical form:
Tablet Prolonged Release
Prescription type:
Product subject to prescription which may be renewed (B)
Authorization status:
Authorised
Authorization number:
PPA1562/036/004
Authorization date:
0000-00-00

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

AdalatRetard10mgProlonged-Releasetablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Onefilm-coated,prolonged-releasetabletcontains10mgnifedipine.

Excipients:containslactose.

Forafulllistofexcipients,seesection6.1.

3PHARMACEUTICALFORM

Film-coated,prolonged-releasetablets

ProductimportedfromtheUK:

Grey-pink,circulartabletsmarkedwithA10ononesideandaBayercrossonthereverse.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Forthemanagementofchronicstableanginapectorisandthetreatmentofmildtomoderatehypertension.

Adalatretard10mgisintendedprimarilyforthetreatmentofmilderformsofcardiovasculardiseasesand,ingeneral,

forthosepatientswho,irrespectiveoftheseverityoftheirdisease,respondparticularlyintenselytonifedipine.In

additionAdalatretard10mgpermitsagradualstarttotreatmentandveryfinelyadjusteddosage.

4.2Posologyandmethodofadministration

Methodofadministration

OralUse

Dosageregimen

Asfaraspossiblethetreatmentmustbetailoredtotheneedsoftheindividualaccordingtotheseverityofthedisease

andthepatient'sresponse.

Dependingontheclinicalpictureineachcase,thebasicdosemustbeintroducedgradually

Adalatretard10mgisparticularlysuitablefordosetitration.Dosetitrationisparticularlyrecommendedfor

hypertensiveswithseverecerebrovasculardiseaseandforpatients,whobecauseoflowbodyweightormultiple

therapieswithotherantihypertensivedrugs,arelikelytohaveanexcessivereactiontonifedipine.Inaddition,patients

inwhomsideeffectsinresponsetothenifedipinetreatmentmakeafinerdoseadjustmentdesirableshouldbe

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Unlessotherwiseprescribed,thefollowingdosageguidelinesapplyforadults:

Incoronaryheartdisease:

Chronicstableangina 1Adalatretard10mgtablettwicedaily

Pectoris

(anginaofeffort) (2x10mg/day)

1Adalatretard20mgtablettwicedaily

(2x20mg/day)

Ifhigherdosagesarenecessary,thedosecanbeincreasedinstagesuptomaximum60mgdaily.

Ifthereisnoadequatetherapeuticresultafter14daysoftreatmentwithAdalatretard10mgorAdalatretard20mg

achangeovershouldbemadetoimmediatereleaseformulations(nifedipinecapsules).

Inhypertension:

1Adalatretard10mgtablettwicedaily

(2x10mg/day)

1Adalatretard20mgtablettwicedaily

(2x20mg/day)

Ifhigherdosagesarenecessary,thedosecanbeincreasedinstagesuptomaximum60mgdaily.

Co-administrationwithCYP3A4inhibitorsorCYP3A4inducersmayresultintherecommendationtoadaptthe

nifedipinedoseornottousenifedipineatall(see“Interactionwithothermedicinalproductsandotherformsof

interaction")..

DurationofTreatment

Theattendingdoctorwilldeterminethedurationofuse.

Duetotheirpronouncedantischemicandantihypertensiveaction,Adalatretardshouldbediscontinuedgradually,

particularlywhenhighdosesareused.

Administration

AsaruleAdalatretardtabletsareswallowedwholewithalittleliquid,irrespectiveofmealtimes.Grapefruitjuiceisto

beavoided(see„Interactionwithothermedicinalproductsandotherformsofinteraction“).

TherecommendeddosageintervalforAdalatretard10mgorAdalatretard20mgisabout12handshouldnotbeless

than4h..

Additionalinformationonspecialpopulations

Paediatricpopulations Thesafetyandefficacyof nifedipine inchildrenbelow18yearshasnotbeen

established. Currentlyavailabledatafortheuseofnifedipineinhypertensionaredescribedinsection5.1.

Geriatricpatients

ThepharmacokineticsofAdalatretardarealteredintheelderlysothatlowermaintenancedosesofnifedipinemaybe

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Patientswithhepaticimpairment

Inpatientswithimpairedliverfunction,carefulmonitoringand,inseverecases,adosereductionmaybenecessary.

Patientswithrenalimpairment

Basedonpharmacokineticdatanodosageadjustmentisrequiredinpatientswithrenalimpairment(see

”Pharmacokineticproperties”)

Thetabletsmustnotbechewedorbrokenup!

4.3Contraindications

Adalatretard10mgshouldnotbeadministeredtopatientswithknownhypersensitivitytonifedipineortoother

dihydropyridinesbecauseofthetheoreticalriskofcross-reactivity.

Adalatretard10mgshouldnotbeadministeredduringpregnancyortonursingmothers.

Adalatretard10mgshouldnotbeusedincaseofcardiogenicshock,clinicallysignificantaorticstenosis,unstable

anginapectoris,orduringorwithinonemonthofamyocardialinfarction.

Adalatretard10mgshouldnotbeusedforthetreatmentofacuteattacksofangina.

ThesafetyofAdalatretard10mginmalignanthypertensionhasnotbeenestablished.

Adalatretard10mgshouldnotbeusedforsecondarypreventionofmyocardialinfarction.

Adalatretard10mgshouldnotbeadministeredconcomitantlywithrifampicinsinceeffectiveplasmalevelsofnifedipine

maynotbeachievedowingtoenzymeinduction(seeSection4.5).

4.4Specialwarningsandprecautionsforuse

Adalatretard10mgisnotabeta-blockerandthereforegivesnoprotectionagainstthedangersofabruptbeta-blocker

withdrawal;anysuchwithdrawalshouldbeagradualreductionofthedoseofbeta-blockerpreferablyover8-10days.

Adalatretard10mgmaybeusedincombinationwithbeta-blockingdrugsandotherantihypertensiveagentsbutthe

possibilityofanadditiveeffectresultinginposturalhypotensionshouldbeborneinmind.Adalatretard10mgwillnot

preventpossiblereboundeffectsaftercessationofotherantihypertensivetherapy.

Adalatretard10mgshouldbeusedwithcautioninpatientswhosecardiacreserveispoor.Deteriorationofheartfailure

hasoccasionallybeenobservedwithnifedipine.

Cautionshouldbeexercisedinpatientswithseverehypotension.

IschaemicpainhasbeenreportedinasmallproportionofpatientswithinonetofourhoursoftheintroductionofAdalat

retard10mgtherapy.Althougha"steal"effecthasnotbeendemonstrated,patientsexperiencingthiseffectshould

discontinueAdalatretard10mg.

DiabeticpatientstakingAdalatretard10mgmayrequireadjustmentoftheircontrol.

Indialysispatientswithmalignanthypertensionandhypovoleamia,amarkeddecreaseinbloodpressurecanoccur.

Therearenosafetyandefficacydatafromwell-controlledstudiesinpregnantwomen(seesection4.6).

Animalstudieshaveshownavarietyofembryotoxic,placentotoxicandfetotoxiceffects(seeSection5.3)when

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Whilstnifedipineiscontra-indicatedinpregnancy,particularcaremustbeexercisedwhenadministeringnifedipinein

combinationwithi.v.magnesiumsulphatetopregnantwomen.

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

nelfinavir,ritonavir,amprenavirandsaquinavirmaytheoreticallyresultinanincreaseinnifedipineplasma

concentrations.Uponco-administrationwithanyofthesecytochromeP4503A4inhibitors,bloodpressureshouldbe

monitoredand,ifnecessary,areductioninthenifedipinedoseconsidered(seeSection4.5).

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

malabsorptionshouldnottakethismedicine.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Drugsthataffectnifedipine.

NifedipineismetabolisedviathecytochromeP4503A4system,locatedbothintheintestinalmucosaandintheliver.

Drugsthatareknowntoeitherinhibitortoinducethisenzymesystemmaythereforealterthefirstpass(afteroral

administration)ortheclearanceofnifedipine(seeSection4.4).

Theextentaswellasthedurationofinteractionsshouldbetakenintoaccountwhenadministeringnifedipinetogether

withthefollowingdrugs:

Rifampicin:

RifampicinstronglyinducesthecytochromeP4503A4system.Uponco-administrationwithrifampicin,the

bioavailabilityofnifedipineisdistinctlyreducedandthusitsefficacyweakened.Theuseofnifedipineincombination

withrifampicinisthereforecontraindicated(seeSection4.3).

Uponco-administrationofweaktomoderateinhibitorsofthecytochromeP4503A4system(listedimmediately

below),thebloodpressureshouldbemonitoredand,ifnecessary,areductioninthenifedipinedoseconsidered

(seeSections4.2and4.4).Inthemajorityofthesecases,noformalstudiestoassessthepotentialforadruginteraction

betweennifedipineandthedrug(s)listedhavebeenundertaken,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

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Nefazodone:

NefazodoneisknowntoinhibitthecytochromeP4503A4mediatedmetabolismofotherdrugs.Thereforeanincrease

innifedipineplasmaconcentrationsuponco-administrationofbothdrugscannotbeexcluded(seeSection4.4).

Quinupristin/dalfopristinandcisapride:

Simultaneousadministrationofquinupristin/dalfopristinandnifedipine,orcisaprideandnifedipine,mayleadto

increasedplasmaconcentrationsofnifedipine(seeSection4.4).

Valproicacid:

Asvalproicacidhasbeenshowntoincreasetheplasmaconcentrationsofthestructurallysimilarcalciumchannel

blocker,nimodipine,duetoenzymeinhibition,anincreaseinnifedipineplasmaconcentrationsandhenceanincrease

inefficacycannotbeexcluded(seeSection4.4).

Cimetidine:

DuetoitsinhibitionofcytochromeP4503A4,cimetidineelevatestheplasmaconcentrationsofnifedipineandmay

potentiatetheantihypertensiveeffect(seeSection4.4).

Furtherstudies

CytochromeP4503A4system-inducinganti-epilepticdrugs,suchasphenytoin,carbamazepineandphenobarbital:

phenytoininducesthecytochromeP4503A4system.Uponco-administrationwithphenytoin,thebioavailability

ofnifedipineisreducedandthusitsefficacyweakened.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(AT-1)receptorantagonists

othercalciumantagonists

alpha-adrenergicblockingagents

PDE5inhibitors

alpha-methyldopa

Whennifedipineisadministeredsimultaneouslywithbeta-receptorblockersthepatientshouldbecarefullymonitored,

sincedeteriorationofheartfailureisalsoknowntodevelopinisolatedcases.

Digoxin:

Thesimultaneousadministrationofnifedipineanddigoxinmayleadtoreduceddigoxinclearanceand,hence,an

increaseintheplasmadigoxinlevel.Thepatientshouldthereforebecheckedforsymptomsofdigoxinoverdosageasa

precautionand,ifnecessary,theglycosidedoseshouldbereducedtakingaccountoftheplasmaconcentrationof

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Quinidine:

Whennifedipineandquinidinehavebeenadministeredsimultaneously,loweredquinidinelevels,or

afterdiscontinuationofnifedipine,adistinctincreaseinplasmaconcentrationsofquinidine,havebeenobservedin

individualcases.Forthisreason,whennifedipineiseitheradditionallyadministeredordiscontinued,monitoringofthe

quinidineplasmaconcentration,andifnecessary,adjustmentofthequinidinedosearerecommended.Someauthors

reportedincreasedplasmaconcentrationsofnifedipineuponco-administrationofbothdrugs,whileothersdidnot

observeanalterationinthepharmacokineticsofnifedipine.

Thereforethebloodpressureshouldbecarefullymonitored,ifquinidineisaddedtoanexistingtherapywithnifedipine.

Ifnecessary,thedoseofnifedipineshouldbedecreased.

Tacrolimus:

TacrolimushasbeenshowntobemetabolisedviathecytochromeP4503A4system.Datarecentlypublishedindicates

thatthedoseoftacrolimusadministeredsimultaneouslywithnifedipinemaybereducedinindividualcases.Uponco-

administrationofbothdrugs,thetacrolimusplasmaconcentrationsshouldbemonitoredand,ifnecessary,areduction

inthetacrolimusdoseconsidered.

Drugfoodinteractions

GrapefruitjuiceinhibitsthecytochromeP4503A4system.Administrationofnifedipinetogetherwithgrapefruitjuice

thusresultsinelevatedplasmaconcentrationsandprolongedactionofnifedipineduetoadecreasedfirstpass

metabolismorreducedclearance.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.

4.6Fertility,pregnancyandlactation

Pregnancy

Adalatretard10mgiscontra-indicatedduringpregnancy.

Adalatretard10mgshouldnotbeusedbywomenwhointendtogetpregnantinthenearfuture.

ThesafetyofAdalatretard10mgforuseinhumanpregnancyhasnotbeenestablished.Evaluationofexperimental

animalstudieshasshownreproductivetoxicityconsistingofembryotoxicityandteratogeniceffectsatmaternallytoxic

doses.

Lactation

AdalatRetard10mgiscontraindicatedinbreastfeeding.Nifedipinepassesintothebreastmilk.Asthereisno

experienceofpossibleeffectsoninfants,breastfeedingshouldfirstbestoppedifnifedipinebecomesnecessaryduring

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In-vitrofertilisation

Insinglecasesofinvitrofertilisationcalciumantagonistslikenifedipinehavebeenassociatedwithreversible

biochemicalchangesinthespermatozoa’sheadsectionthatmayresultinimpairedspermfunction.Inthosemenwho

arerepeatedlyunsuccessfulinfatheringachildbyinvitrofertilisation,andwherenootherexplanationcanbefound,

calciumantagonistslikenifedipineshouldbeconsideredaspossiblecauses.

4.7Effectsonabilitytodriveandusemachines

Reactionstothedrug,whichvaryinintensityfromindividualtoindividual,canimpairtheabilitytodriveortooperate

machinery.Thisappliesparticularlyatthestartoftreatment,onchangingthemedicationandincombinationwith

alcohol.

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”wereobservedwitha

frequencybelow3%withtheexceptionofoedema(9.9%)andheadache(3.9%).

ThefrequenciesofADRsreportedwithnifedipinecontainingproductsaresummarisedinthetablebelow.Withineach

frequencygrouping,undesirableeffectsarepresentedinorderofdecreasingseriousness.Frequenciesaredefinedas

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

onlyduringtheongoingpostmarketingsurveillance,andforwhichafrequencycouldnotbeestimated,arelistedunder

“Notknown”.

SystemOrganClass

(MedDRA) Common Uncommon Rare VeryRare

Bloodand

lymphaticsystem

disorders Agranulocytosis

Leukopenia

Immunesystem

disorders Allergicreaction

Allergicoedema/

angioedema(incl.

larynxoedema*) 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 Visual

disturbances Eyepain

Cardiacdisorders Tachycardia

Palpitations Chestpain

(Angina

pectoris)

Vasculardisorders Oedema

Vasodilation Hypotension

Syncope

Respiratory,

thoracic,and

mediastinal

disorders Nosebleed

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*=Mayresultinlifethreateningoutcome.

Indialysispatientswithmalignanthypertensionandhypovolaemiaadistinctfallinbloodpressurecanoccurasaresult

ofvasodilation.

4.9Overdose

Symptoms

Thefollowingsymptomsareobservedincasesofseverenifedipineintoxication:

Disturbancesofconsciousnesstothepointofcoma,adropinbloodpressure,tachycardiac/bradycardiacheartrhythm

disturbances,hyperglycaemia,metabolicacidosis,hypoxia,cardiogenicshockwithpulmonaryoedema.

ManagementofOverdose

Asfarastreatmentisconcerned,eliminationoftheactivesubstanceandtherestorationofstablecardiovascular

conditionshavepriority.

Afteroralingestion,thoroughgastriclavageisindicated,ifnecessaryincombinationwithirrigationofthesmall

intestine.

Particularlyincasesofintoxicationwithslow-releasenifedipineformulations,suchasAdalatretard10mgand20mg,

eliminationmustbeascompleteaspossible,includingthesmallintestine,topreventtheotherwiseinevitable

subsequentabsorptionoftheactivesubstance.

Haemodialysisservesnopurpose,asnifedipineisnotdialysable,butplasmapheresisisadvisable(highplasmaprotein

binding,relativelylowvolumeofdistribution).

Hypotensionasaresultofcardiogenicshockandarterialvasodilatationcanbetreatedwithcalcium(10-20mlofa10

Gastrointestinal

disorders Constipation Gastrointestinal

abdominalpain

Nausea

Dyspepsia

Flatulence

Drymouth Gingival

hyperplasia Vomiting

Gastrooesophageal

sphincter

insufficiency

Hepatobiliary

disorders Transientincrease

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 Erectile

dysfunction

Generaldisorders

andadministration

siteconditions Feelingunwell Unspecificpain

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Asaresult,theserumcalciumcanreachtheuppernormalrangetoslightlyelevatedlevels.Ifaninsufficientincreasein

bloodpressureisachievedwithcalcium,vasoconstrictingsympathomimeticssuchasdopamineornoradrenalineshould

beadministered.Thedosageofthesedrugsshouldbedeterminedbythepatient'sresponse.

Symptomaticbradycardiamaybetreatedwithbeta-sympathomimetics,andinlife-threateningbradycardiac

disturbancesofheartrhythm,temporarypacemakertherapymaybeadvisable.

Additionalliquidorvolumemustbeadministeredwithcautionbecauseofthedangerofoverloadingtheheart.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

ATCcode:C08CA05

Nifedipineisaspecificandpotentcalciumantagonistofthe1,4-dihydropyridinetype.Calciumantagonistsreducethe

transmembranalinfluxofcalciumionsthroughtheslowcalciumchannelintothecell.Nifedipineactsparticularlyon

thecellsofthemyocardiumandthesmoothmusclecellsofthecoronaryarteriesandtheperipheralresistancevessels.

Inhypertension,themainactionofAdalatretard10mgistocauseperipheralvasodilatationandthusreduceperipheral

resistance.Inangina,Adalatretard10mgreducesperipheralandcoronaryvascularresistance,leadingtoanincreasein

coronarybloodflow,cardiacoutputandstrokevolume,whilstdecreasingafter-load.

Additionally,nifedipinedilatessubmaximallybothclearandatheroscleroticcoronaryarteries,thusprotectingtheheart

againstcoronaryarteryspasmandimprovingperfusiontotheischaemicmyocardium.

NifedipinereducesthefrequencyofpainfulattacksandtheischaemicECGchangesirrespectiveoftherelative

contributionfromcoronaryarteryspasmoratherosclerosis.

Adalatretard10mgadministeredtwice-dailyprovides24-hourcontrolofraisedbloodpressure.

Adalatretard10mgcausesreductioninbloodpressuresuchthatthepercentageloweringisdirectlyrelatedtoits

initiallevel.Innormotensiveindividuals,Adalatretard10mghaslittleornoeffectonbloodpressure.

InRaynaud'ssyndromenifedipinecanpreventorreducetheoccurringdigitalvasospasm.

Paediatricpopulations:

Limitedinformationoncomparisonofnifedipinewithotherantihypertensivesisavailableforbothacutehypertension

andlong-termhypertensionwithdifferentformulationsindifferentdosages.AntihypertensiveeffectsofNifedipine

havebeendemonstratedbutdoserecommendations,longtermsafetyandeffectoncardiovascularoutcomeremain

unestablished.Paediatricdosingformsarelacking.

5.2Pharmacokineticproperties

Absorption

Afteroraladministrationnifedipineisrapidlyandalmostcompletelyabsorbed.Thesystemicavailabilityoforally

administerednifedipineis45-56%owingtoafirstpasseffect.Maximumplasmaandserumconcentrationarereached

at1.5to4.2hourswithAdalatretard20mgtablets.Simultaneousfoodintakeleadstodelayed,butnotreduced

absorption.

Distribution

Nifedipineisabout95%boundtoplasmaprotein(albumin).Thedistributionhalf-lifeafterintravenousadministration

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Biotransformation

Afteroraladministrationnifedipineismetabolizedinthegutwallandintheliver,primarilybyoxidativeprocesses.

Thesemetabolitesshownopharmacodynamicactivity.Nifedipineisexcretedintheformofitsmetabolites

predominantlyviathekidneysandabout5-15%viathebileinthefaeces.Theunchangedsubstanceisrecoveredonly

intraces(below0.1%)intheurine.

Elimination

Theterminaleliminationhalf-lifeis6-11hours(Adalatretard),becauseofdelayedabsorption.Noaccumulationof

thesubstanceaftertheusualdosewasreportedduringlong-termtreatment.Incasesofimpairedkidneyfunctionno

substantialchangeshavebeendetectedincomparisonwithhealthyvolunteers.Incasesofimpairedliverfunctionthe

eliminationhalf-lifeisdistinctlyprolongedandthetotalclearanceisreduced.Adosereductionmaybenecessaryin

severecases.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsingleandrepeateddosetoxicity,

genotoxicityandcarcinogenicpotential.

Reproductiontoxicology

Nifedipinehasbeenshowntoproduceteratogenicfindingsinrats,miceandrabbits,includingdigitalanomalies,

malformationoftheextremities,cleftpalatescleftsternum,andmalformationoftheribs.Digitalanomaliesand

malformationoftheextremitiesarepossiblyaresultofcompromiseduterinebloodflow,buthavealsobeenobserved

inanimalstreatedwithnifedipinesolelyaftertheendoftheorganogenesisperiod.

Nifedipineadministrationwasassociatedwithavarietyofembryotoxic,placentotoxicandfetotoxiceffects,including

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

fetaldeaths(rats,mice,rabbits)andprolongedpregnancy/decreasedneonatalsurvival(rats;notevaluatedinother

species).

Allofthedosesassociatedwiththeteratogenic,embryotoxicorfetotoxiceffectsinanimalswerematernallytoxic

atseveraltimestherecommendedmaximumdoseforhumans(seesection4.6).

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Microcrystallinecellulose

Polysorbate80

Hypromellose

Lactose

Maizestarch

Macrogol

Magnesiumstearate

Titaniumdioxide(E171)

Ironoxide(E172)

6.2Incompatibilities

Notapplicable.

6.3Shelflife

Theshelflifeexpirydateforthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

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6.4Specialprecautionsforstorage

Storeintheoriginalcontainerinordertoprotectfromlight.

6.5Natureandcontentsofcontainer

Blisterstripsoftabletsinacardboardoutercontainer,inpacksof56tablets.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements.

7PARALLELPRODUCTAUTHORISATIONHOLDER

LTTPharmaLimited

Unit18OxleasowRoad

EastMoonMoat

Redditch

WorcestershireB980RE

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1562/36/4

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12 th

November2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

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Date Printed 21/11/2012 CRN 2116807 page number: 11

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