FELODIPINE

Main information

  • Trade name:
  • FELODIPINE Tablet Prolonged Release 2.5 Milligram
  • Dosage:
  • 2.5 Milligram
  • Pharmaceutical form:
  • Tablet Prolonged Release
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • FELODIPINE Tablet Prolonged Release 2.5 Milligram
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PA0711/135/001
  • Authorization date:
  • 22-08-2008
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

IRISHMEDICINESBOARDACTS1995AND2006

MEDICINALPRODUCTS(CONTROLOFPLACINGONTHEMARKET)REGULATIONS,2007

(S.I.No.540of2007)

PA0711/135/001

CaseNo:2037713

TheIrishMedicinesBoardinexerciseofthepowersconferredonitbytheabovementionedRegulationsherebygrantsto

RowexLtd

Bantry,Co.Cork,Ireland

anauthorisation,subjecttotheprovisionsofthesaidRegulations,inrespectoftheproduct

Felodipine2.5mgprolongedreleasetablets

TheparticularsofwhicharesetoutinPartIandPartIIoftheattachedSchedule.Theauthorisationisalsosubjecttothegeneralconditionsas

maybespecifiedinthesaidRegulationsaslistedonthereverseofthisdocument.

Thisauthorisation,unlesspreviouslyrevoked,shallcontinueinforcefrom22/08/2008until21/08/2013.

SignedonbehalfoftheIrishMedicinesBoardthis

________________

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 1

PartII

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

Felodipine2.5mgprolongedreleasetablets

2QUALITATIVEANDQUANTITATIVECOMPOSITION

Oneprolongedreleasetabletcontains2.5mgfelodipine.

Excipient:lactosemonohydrate48.77mg/prolongedreleasetablet

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Prolongedreleasetablet

Round,biconvexfilm-coated-tablets,paleyellow;embossment“2.5”ononesideofthetablet.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Essentialhypertension

4.2Posologyandmethodofadministration

Fororaladministration

Thedoseshouldbeadjustedtotheindividualrequirementsofthepatient.Felodipineshouldusuallybeadministeredas

follows:Therecommendedinitialdoseis5mgfelodipineoncedaily.Ifnecessarythedosemaybeincreasedto10mg

felodipineoncedailyoranotherantihypertensiveagentadded.

Doseincreasesshouldoccuratintervalsofatleast2weeks.Theusualmaintenancedoseis5-10mgoncedaily.

Themaximumdailydoseis10mgfelodipine.Inelderlypatientsaninitialtreatmentwith2.5mgdailyshouldbe

considered.Subsequentdoseincreasesshouldbeundertakenwithparticularcaution.

Impairedrenalfunction

Thepharmacokineticsisnotsignificantlyaffectedinpatientswithmildtomoderateimpairedrenalfunction.Caution

shouldbetakeninpatientswithsevererenalimpairment(seesections4.4and5.2).

Impairedhepaticfunction

Inpatientswithmildtomoderatehepaticimpairment,therecommendedinitialdoseshouldbeloweredtotheminimal

therapeuticeffectivedoseoffelodipine.Thedoseshouldonlybeincreasedaftercarefullybalancingthebenefitsagainst

therisks(seesection5.2).Itiscontraindicatedinpatientswithseverehepaticimpairment.

Childrenandadolescents(lessthan18yearsofage)

Felodipineisnotrecommendedforuseinchildrenandadolescents(lessthan18yearsofage)duetoinsufficientdataon

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 2

Methodofadministration

Theprolongedreleasetabletsshouldbetakeninthemorningwithasufficientamountoffluid(e.g.aglassofwater,but

shouldNOTbetakenwithgrapefruitjuice!)(seesection4.5).

Theprolongedreleasetabletsshouldbeswallowedwholeandnotchewedorcrushed.

Thetabletsmaybetakenonemptystomachorwithalightmeal,howeverahigh-fatmealshouldbeavoided(seesection

5.2).

4.3Contraindications

Felodipineiscontraindicatedinpatients:

withhypersensitivitytofelodipine(orotherdihydropyridines)ortoanyoftheexcipients

withcardiogenicshock(aswithothercalciumchannelblockers,treatmentshouldbediscontinuedinpatientswho

developcardiogenicshock)

withsevereaorticormitralstenosis

withobstructivehypertrophiccardiomyopathy

withunstableanginapectoris

whohavehadanacutemyocardialinfarction(within4-8weeksofamyocardialinfarction)

withdecompensatedheartfailure

withseverehepaticimpairment

duringpregnancy

4.4Specialwarningsandprecautionsforuse

Felodipineshouldbeusedwithcautioninpatientswith:

conductiondisorders,compensatedheartfailure,tachycardiaandaorticormitralvalvestenosis

severeleftventriculardysfunction

mildtomoderatehepaticimpairment,astheanti-hypertensiveeffectmaybeenhanced.Adjustmentofthedosage

shouldbeconsidered

severerenalimpairment(GFR<30ml/min)

AVblockofthesecondorthirddegree

Iftreatmentwithfelodipineisdiscontinuedabruptly,ahypertensivecrisismayoccurinindividualcases.

Felodipinecouldcausesignificanthypotension(vasodilationeffect)withconsecutivetachycardia,leadingtomyocardial

ischaemiainsusceptiblepatients.Thismayleadtomyocardialinfarction(seesection5.1).

Dihydropyridinesmaycauseacutehypotension.Insomecasesthereisariskofhypoperfusionaccompaniedbyreflex

tachycardia(paradoxicalanginapectoris)(seesection5.1).

FelodipineismetabolisedbyCYP3A4enzymes.Therefore,combinationwithmedicinalproductswhicharepotent

CYP3A4inhibitorsorinducersshouldbeavoided(seesection4.5).Duetothesamereasontheconcomitantintakeof

grapefruitjuiceshouldbeavoided(seesection4.5).

Aswiththeuseofothercalciumantagonists,inpatientswithseriousgingivitisorperiodontitistherehavebeen

reportsofmildgingivalhyperplasia.Thishyperplasiacanbeavoidedoratleastmitigatedbycarefulattentiontodental

hygiene.

Patientswithrarehereditaryproblemsofgalactoseintolerance,theLapplactasedeficiencyorglucose-galactose

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 3

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

FelodipineisaCYP3A4substrate.MedicinalproductsthatinduceorinhibitCYP3A4willhavelargeinfluenceon

felodipineconcentrations.

TheconcomitantintakeoffelodipineandmedicinalproductswhichinhibitthecytochromeP450isoenzyme3A4ofthe

liver(suchascimetidine,azoleantifungals(itraconazole,ketoconazole),macrolideantibiotics(erythromycin),

telithromycinorHIVproteaseinhibitors)leadstoincreasedfelodipineplasmalevels(seesection4.4).During

concomitantadministrationoffelodipinewithitraconazole,C

increased8-foldandAUC6-fold.During

concomitantadministrationoffelodipinewitherythromycin,C

andAUCincreasedapproximately2.5-fold.

CombinationwithpotentCYP3A4inhibitorsshouldbeavoided.

GrapefruitjuiceinhibitscytochromeP4503A4.Concomitantadministrationoffelodipinewithgrapefruitjuice

increasedfelodipineC

andAUCapproximately2-fold.Thecombinationshouldalsobeavoided.

Concomitanttreatmentwithdrugssuchascarbamazepine,phenytoinandbarbiturates(e.g.phenobarbital)and

rifampicinreducestheplasmalevelsoffelodipineviaenzymeinductionintheliver(cytochromeP450-system).During

concomitantadministrationoffelodipinwithcarbamazepin,phenytoin,phenobarbital,AUCdecreasedby93%and

by82%.AsimilareffectisexpectedwithSt.John`swort.Thereforeadoseincreaseoffelodipinemaybe

necessary.CombinationwithCYP3A4inducersshouldbeavoided.

Theanti-hypertensiveeffectoffelodipinemaybeenhancedbyotheranti-hypertensivesandtricyclicantidepressants.

Duetoaninitialsaliureticeffect,felodipinecanenhanceapre-existinghypokalemiawhenaddedtodiuretictherapy.

Hydrochlorothiazidemayenhancetheanti-hypertensiveeffectoffelodipine.

FelodipinecaninduceanincreaseofC

ofcyclosporine.Additionally,cyclosporinemayinhibitfelodipine

metabolismwhichmaycreateapotentialrisktofelodipinetoxicity.Concomitantadministrationofcyclosporineand

felodipineincreasedfelodipinec

2.5foldandAUC1.6fold.

Felodipinemayincreasetheconcentrationoftacrolimus.Whenusedtogether,thetacrolimusserumconcentratrion

shouldbefollowedandthetacrolimusdosemayneedtobeadjusted.

Bloodlevelsofdigoxinincreaseduringconcomitantadministrationoffelodipine.Thereforedecreasingofdigoxin

dosageshouldbetakenintoaccountwhenthetwodrugsareadministeredconcurrently.

Felodipinedoesnotappeartoaffecttheunboundfractionofotherextensivelyplasmaproteinbounddrugssuchas

warfarin.

4.6Pregnancyandlactation

Felodipineiscontraindicatedthroughoutpregnancy,asanimalexperimentshavedemonstratedfoetaldamage(see

section5.3).Pregnancymustbeexcludedbeforestartingtreatmentwithfelodipine.

Felodipineisexcretedinbreastmilk.Ifthebreast-feedingmotheristakingtherapeuticdosesoffelodipine,atotally

breast-fedinfantabsorbsonlyaverylowdoseoftheactivesubstancewiththebreastmilk.Thereisnoexperienceof

theriskthismayposetothenewborn,therefore,asaprecaution,breastfeedingshouldbediscontinuedduring

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 4

4.7Effectsonabilitytodriveandusemachines

Treatmentwithfelodipinerequiresregularmedicalsupervision.Inindividualcasesfelodipinecaninfluenceapatients

reactionstosuchextentthatthe

abilitytodriveortooperatemachinesortoworkwithoutsuitablesafeguardsmaybeimpaired.Thisisparticularlythe

caseatthestartoftherapyorwhenthedoseisincreased,orwhenthedoseischangedaswellasafterconcomitant

ingestionofalcohol.

4.8Undesirableeffects

Thefollowingterminologieshavebeenusedinordertoclassifytheoccurrenceofundesirableeffects:

Verycommon( ≥1/10)

Common( ≥1/100to<1/10)

Uncommon( ≥1/1000to<1/100)

Rare( ≥1/10,000to<1/1,000)

Veryrare(<1/10,000),notknown(cannotbeestimatedfromtheavailabledata)

Cardiacdisorders

Common:Particularlyatthebeginningoftreatment,anginapectorisattacksmayoccur,orinpatientswithpre-existing

anginapectoristheremaybeanincreaseinthefrequency,durationandseverityoftheattacks.

Uncommon:Palpitations,tachycardia,hypotension.

Veryrare:Myocardialinfarction

Nervoussystemdisorders

Verycommon:Headache(particularlyatthebeginningoftreatment,whenthedoseisincreasedorwhenhighdosesare

administered).Generally,thiseffectsubsidesoncontinuedtreatment.

Uncommon:Paraesthesia,dizziness,fatigue,syncope,restlessness

Earandlabyrinthdisorders

Verycommon:Tinnitus(particularlyatthebeginningoftreatment,whenthedoseisincreasedorwhenhighdosesare

administered).Generally,thiseffectsubsidesoncontinuedtreatment.

Respiratory,thoracicandmediastinaldisorders

Uncommon:Dyspnoea

Gastrointestinaldisorders

Uncommon:Nausea,vomiting,diarrhoea,constipation

Renalandurinarydisorders

Uncommon:Pollakiuria(increasedurinaryfrequency)

Skinandsubcutaneoustissuedisorders

Verycommon:Flushing(particularlyatthebeginningoftreatment,whenthedoseisincreasedorwhenhighdosesare

administered).Generally,thiseffectsubsidesoncontinuedtreatment.

Uncommon:Skinandhypersensitivityreactionssuchaspruritus,urticaria,exanthema,photosensitisation.

Gingivalhyperplasiaandgingivitis

Veryrare:Exfoliativedermatitis

Musculoskeletalandconnectivetissuedisorders

Uncommon:Myalgia,arthralgia,tremors

Vasculardisorders

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 5

Generaldisordersandadministrationsiteconditions

Common:Peripheraloedema(Thedegreeofankleswellingisdoserelated.)

Uncommon:Weightgain,sweating

Veryrare:Angiooedema,fever

Hepatobiliarydisorders

Veryrare:Hepaticfunctiondisorders(elevatedtransaminaselevels)

Reproductivesystemandbreastdisorders

Veryrare:Erectiondisorders,gynaecomastia,menorrhagia

4.9Overdose

Symptomsofoverdose

Overdosemayleadtoexcessiveperipheralvasodilationandthenmarkedhypotensionandinrarecasesbradycardia.

Managementofoverdose

Thetherapeuticmeasuresshouldbefocusedontheeliminationoftheactiveingredientandtherestorationofthe

circulation.

Activatedcharcoal,inductionofvomitingorgastriclavageifappropriateorindicateshouldbeconsidered.

Ifseverehypotensionoccurs,symptomatictreatmentshouldbeprovided,thepatientshouldbeplacedsupinewiththe

legselevated.Incaseofaccompanyingbradycardiaatropine(0.5-1.0mg)shouldbegivenintravenously.Additional

intravenousfluidsshouldbecautiouslyadministeredunderhaemodynamicsupervisiontopreventcardiacoverloading.

Sympathomimeticdrugswithpredominanteffectonthe

-adrenoreceptor(suchasdobutamine,dopamine,

norepinephrineoradrenaline)mayalsobegiven.Dosagedependsontheefficacyobtained.

Felodipineisonlydialysabletominimalextent(approx.9%).

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Pharmacotherapeuticgroup:1,4-dihydropyridinederivative/calciumantagonist

ATCcode:C08CA02

Felodipineisacalciumantagonistofthedihydropyridineclass.Calciumantagonistsinterferewiththevoltage-

dependentL-type(slow)calciumchannelsintheplasmamembranesofsmoothmusclecellsandreducetheinflowof

calciumions.Thisresultsinvasodilation.

Felodipineisavasoselectivecalciumantagonist:ithasastrongereffectonthevascularsmoothmusclethanthe

myocardialmuscle.Felodipineselectivelydilatesarterioleswithnoeffectonvenousvessels.

Felodipineleadstoadose-relatedloweringofthebloodpressureviavasodilationandconsequentlyareductionof

peripheralvascularresistance.Itreducesbothsystolicanddiastolicbloodpressure.Thehemodynamiceffectof

felodipineisaccompaniedbyreflex(baroreceptor-mediated)tachycardia.Reflextachycardiaisuncommoninthis

prolongedreleaseproduct,inparticularduringchronicuse.

Intherapeuticdoses,felodipinehasnodirecteffectineithercardiaccontractilityorcardiacconduction.Felodipine

reducesrenalvascularresistance.Theglomerularfiltrationrateremainsunchanged.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 6

Felodipinecanbeusedasamonotherapybutalsoconcomitantlywithbeta-blockers,diureticsandACE-inhibitors.

5.2Pharmacokineticproperties

Absorption

Felodipineiscompletelyabsorbedfollowingoraladministration.Withtheextendedreleasetabletstheabsorptionphase

isprolonged.Thisresultsinevenfelodipineplasmaconcentrationswithinthetherapeuticrangeover24hours.Peak

plasmalevelsarereachedafter3-5hours.Steady-stateisreachedapproximately3daysafterstartingtreatment.Dueto

anexcessivefirst-passeffect,onlyapproximately15%oftheadministereddoseissystemicallyavailable.

Distribution

Theplasmaproteinbindingoffelodipineis>99%.Thevolumeofdistributionisapproximately10l/kgatsteadystate,

sothatfelodipineisindicatingalargetissuedistribution.Thereisnosignificantaccumulationduringlong-term

treatment.

Metabolism

FelodipineisextensivelymetabolisedintheliverbyCYP3A4.Allidentifiedmetabolitesareinactive.

Elimination

Nounchangedparentsubstanceisdetectableintheurine.Theaveragehalf-lifeoffelodipineintheterminalphaseis25

hours.Theinactivehydrophilicmetabolitesformedbyhepaticbiotransformationaremainlyeliminatedrenally(to

approx.70%),andtheremainderisexcretedinthefeces.

Themeanplasmaclearanceis1100ml/minanddependsonthehepaticbloodflow.

Elderly

Increasedplasmaconcentrationshavebeenmeasuredinelderlypatients.

Impairedhepaticfunction

Increasedplasmaconcentrationsofupto100%havebeenmeasuredinpatientswithimpairedhepaticfunction.

Impairedrenalfunction

Renalimpairmentdoesnotaffectthepharmacokineticsoffelodipine,althoughaccumulationofinactivemetabolites

occursinrenalfailure.

Effectoffood

Accordingtostudiesperformedwithfelodipinetabletsahigh-fatmealmayhaveanimpactonpharmacokinetic

parameters.

5.3Preclinicalsafetydata

Preclinicaldatarevealnospecialhazardforhumansbasedonconventionalstudiesofsafetypharmacology,repeated

dosetoxicity,genotoxicityandcarcinogenicpotential.Inanimalstudieswithrespecttothereproductionadverseeffects

werefound.Effectsinrats(prolongeddurationofpregnancyanddifficultlabour)andrabbits(impaireddevelopmentof

distalphalanges,presumablyduetodecreaseduteroplacentalperfusion)revealednoevidenceofadirectteratogenic

effect,butindicatesecondaryconsequencesofthepharmacodynamiceffect.Inmonkeysanabnormalpositionofthe

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 7

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Tabletcore:

Lactosemonohydrate

Sodiumlaurilsulfate

Hypromellose

Microcrystallinecellulose

Magnesiumstearate

Tabletcoating:

Lactosemonohydrate

Hypromellose

Titaniumdioxide(E171)

Macrogol4000

Ironoxide,yellow(E172)

6.2Incompatibilities

Notapplicable

6.3ShelfLife

Blisterandtabletcontainer

5years

Tabletcontainer

Shelflifeafterfirstopening:6months.

6.4Specialprecautionsforstorage

Thismedicinalproductdoesnotrequireanyspecialstorageconditions.

Tabletcontainer:Storageconditionafterfirstopening:Donotstoreabove25°C.

6.5Natureandcontentsofcontainer

PVC/Aluminiumblisterswith7,14,20,28,30,50,56,60,100and112prolonged-releasetablets

Polyethylenecontainerswithpolyethyleneclosurescontaining100and250prolonged-releasetablets

Notallpacksizesmaybemarketed.

6.6Specialprecautionsfordisposalandotherhandling

Nospecialrequirements

7MARKETINGAUTHORISATIONHOLDER

RowexLtd.,

Bantry,

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 8

8MARKETINGAUTHORISATIONNUMBER

PA711/135/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:22ndAugust2008

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 29/09/2008 CRN 2037713 page number: 9