DILZEM XL

Main information

  • Trade name:
  • DILZEM XL
  • Dosage:
  • 240 Milligram
  • Pharmaceutical form:
  • Prolonged Release Capsules
  • Medicine domain:
  • Humans
  • Medicine type:
  • Allopathic drug

Documents

Localization

  • Available in:
  • DILZEM XL
    Ireland
  • Language:
  • English

Status

  • Source:
  • HPRA - Health Products Regulatory Authority - Ireland
  • Authorization number:
  • PPA1562/026/001
  • Authorization date:
  • 12-11-2010
  • Last update:
  • 14-10-2016

Summary of Product characteristics: dosage, interactions, side effects

SummaryofProductCharacteristics

1NAMEOFTHEMEDICINALPRODUCT

DilzemXL240mgProlonged-releaseHardCapsules

2QUALITATIVEANDQUANTITATIVECOMPOSITION

EachDilzemXL240mgcapsulecontainsdiltiazemhydrochloride240mg.

Excipients:Eachcapsulecontainssucrose.

Forafulllistofexcipients,seesection6.1

3PHARMACEUTICALFORM

Prolonged-releasecapsules,hard

ProductimportedfromGermany

White,hardgelatincapsules,printedwith‘D240mg’andcontainingroughlysphericalwhitetooff-whitebeads.

4CLINICALPARTICULARS

4.1TherapeuticIndications

Prophylaxisandtreatmentofanginapectoris.

Treatmentofmildtomoderatehypertension.

4.2Posologyandmethodofadministration

Oraluseonly.

Adults:

Hypertension:Theusualinitialdoseisone180mgcapsuleperday(correspondingto180mgofdiltiazem

hydrochloride).Dependinguponclinicalresponsethepatient’sdosagemaybeincreased

stepwiseto360mg/dayifrequired.

AnginaPectoris:Theusualinitialdoseisone180mgcapsuleperday(correspondingto180mgofdiltiazem

hydrochlorideoncedaily).Dependinguponclinicalresponsethepatient’sdosagemaybeincreasedstepwiseto

360mg/dayifrequired.

Elderlypatientsandthosewithrenalorhepaticimpairment:

Dosageshouldcommenceatthelowerlevelof120mgonce-dailyandbeincreasedslowly.Donotincreasethedoseif

theheartratefallsbelow50beatsperminute.

Children:

Thisproductisnotrecommendedforuseinchildren.

4.3Contraindications

Useinwomenofchild-bearingpotential.

Concomitantadministrationofdantroleneinfusionduetotheriskofventricularfibrillation.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 1

Acutecardiacinfarctwithcomplications(bradycardia,severehypotension,leftheartinsufficiency).

Bradycardia(pulserate,atrest,oflessthan50perminute),hypotension(lessthan90mmHgsystole),secondor

thirddegreeheartblockorsicksinussyndrome,exceptinthepresenceofafunctioningventricularpacemaker.

Atrialfibrillation/flutterandsimultaneouspresenceofaWPW(Wolff-Parkinson-White)syndrome(increasedrisk

oftriggeringaventriculartachycardia).

Manifestmyocardialinsufficiency.

Leftventricularfailurewithstasis.

Hypersensitivitytodiltiazemoranyoftheexcipients.

4.4Specialwarningsandprecautionsforuse

Capsulesshouldnotbesuckedorchewed.

Theuseofdiltiazemhydrochlorideindiabeticpatientsmayrequireadjustmentoftheircontrol.

Priortogeneralanaesthesia,theanaesthetistmustbeinformedofongoingdiltiazemtreatment(seesection4.5).

Increaseofplasmaconcentrationsofdiltiazemmaybeobservedintheelderlyandinpatientswithrenalorhepatic

insufficiency.Thecontraindicationsandprecautionsshouldbecarefullyobservedandclosemonitoring,

particularlyofheartrate,shouldbecarriedoutatthebeginningoftreatment.

Theproductshouldbeusedwithcautioninpatientswithhepaticdysfunction.Abnormalitiesofliverfunctionmay

occurduringtherapy.Veryoccasionalreportsofabnormalliverfunctionhavebeenreceived;thesereactionshave

beenreversibleupondiscontinuationoftherapy.

FirstdegreeAVblockorprolongedPRinterval.DILZEMprolongsAVnoderefractoryperiodswithoutsignificantly

prolongingsinusnoderecoverytime,exceptinpatientswithsicksinussyndrome.Thiseffectmayrarelyresultin

abnormallyslowheartrates(particularlyinpatientswithsicksinussyndrome)orsecondorthirddegreeAVblock

(seesection4.5interactionssectionforinformationconcerningbeta-blockersanddigitalis).

Closeobservationisnecessaryinpatientswithreducedleftventricularfunctionandbradycardia(riskof

exacerbation)(seesection4.3).

Diltiazemisnotrecommendedforuseinpatientswithacuteporphyriaunlessothersaferalternativesarenot

available.

Therehavebeenliteraturereportsofcalcium-channelblockers,includingdiltiazem,exacerbatingmuscleweakness

inpatientswithmyastheniagravis,withpotentiallyclinicallysignificantconsequencessuchasrespiratoryfailure.

Likeothercalciumchannelantagonists,diltiazemhasaninhibitoryeffectonintestinalmotility.Thereforeitshould

beusedwithcautioninpatientsatrisktodevelopanintestinalobstruction.

Residuesfromslowreleaseformulationsoftheproductmaypassintothepatient’sstools;however,thisfindinghas

noclinicalrelevance.

Calciumchannelblockingagents,suchasdiltiazem,maybeassociatedwithmoodchanges,includingdepression.

Owingtothepresenceofsucrose,patientswithrarehereditaryproblemsoffructoseintolerance,glucose-galactose

malabsorptionorsucrase-isomaltaseinsufficiencyshouldnottakethismedicine.

Aswithanydruggivenoverprolongedperiods,laboratoryparametersshouldbemonitoredatregularintervals.

4.5Interactionwithothermedicinalproductsandotherformsofinteraction

Concomitantusecontraindicated:

Dantrolene(infusion):Lethalventricularfibrillationisregularlyobservedinanimalswhenintravenousverapamiland

dantroleneareadministeredconcomitantly.Thecombinationofacalciumantagonistanddantroleneistherefore

potentiallydangerous(seesection4.3).

Concomitantuserequiringcaution:

Anaesthetics:Anaesthetistsshouldbewarnedthatapatientistakingdiltiazem.Thedepressionofcardiaccontractility,

conductivityandautomaticityaswellasthevasculardilationassociatedwithanaestheticsmaybepotentiatedby

calciumchannelblockers.

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 2

Statins:DuetometabolicinteractionviaCYP3A4,treatmentwithHMGCoAreductaseinhibitorssuchassimvastatin,

atorvastatinorlovastatin,incombinationwithdiltiazem,shouldbestartedatthelowestpossibledoseandtitrated

upwards.IfapatientisalreadytakinganHMGCoAreductaseinhibitorareductioninthatdoseshouldbeconsidered

andretitrationagainstserumcholesterolconcentrationscarriedout.Patientmonitoringforsignsandsymptomsof

rhabdomyolysisandmyopathyisrecommended.CYP3A4isnotinvolvedinthemetabolismoffluvastatin,pravastatin

androsuvastatin.

Lithium:Riskofincreaseinlithium-inducedneurotoxicity.

Warfarin:Therehavebeenreportsintheliteratureofdiltiazeminteractionswithwarfarin.

Nitratederivatives:Increasedhypotensiveeffectsandfaintness(additivevasodilatatingeffects):Inallthepatients

treatedwithcalciumantagonists,theprescriptionofnitratederivativesshouldonlybecarriedoutatgradually

increasingdoses.

Theophylline:Increaseincirculatingtheophyllinelevels.Itisrecommendedthattheplasmatheophylline

concentrationsbeassayedandthatthedoseshouldbeadjustedifnecessary.

Alpha-antagonists:Increasedantihypertensiveeffects:

Concomitanttreatmentwithalpha-antagonistsmayproduceoraggravatehypotension.Thecombinationofdiltiazem

withanalpha-antagonistshouldbeconsideredonlywiththestrictmonitoringofthebloodpressure.

Amiodarone,digoxin:Increasedriskofbradycardia:

Cautionisrequiredwhenthesearecombinedwithdiltiazem,particularlyinelderlysubjectsandwhenhighdosesare

used.

AmiodaroneincombinationwithdiltiazemmayalsocauseAVblockandmyocardialdepression.

Itisrecommendedthattheplasmadigoxinconcentrationsbeassayedandthatthedoseshouldbeadjustedifnecessary.

CardiacglycosidesmaycauseagreaterdegreeofAVblocking,reducetheheartrateorinduceahypotensiveeffect.

Beta-blockers:Possibilityofrhythmdisturbances(pronouncedbradycardia,sinusarrest),sino-atrialand

atrioventricularconductiondisturbancesandheartfailure(synergisticeffect).Suchacombinationmustonlybeused

undercloseclinicalandECGmonitoring,particularlyatthebeginningoftreatment.

Otherantiarrhythmicagents:

Sincediltiazemhasantiarrhythmicproperties,itsconcomitantprescriptionwithotherantiarrhythmicagentsisnot

recommended(additiveriskofincreasedcardiacadverseeffects).Thiscombinationshouldonlybeusedunderclose

clinicalandECGmonitoring.

Diuretics,ACEinhibitorsorotherantihypertensiveagents:

Patientsshouldbecarefullymonitoredwhentakingdiltiazemconcomitantlywiththeseagents.

Carbamazepine:Increaseincirculatingcarbamazepinelevels:

Itisrecommendedthattheplasmacarbamazepineconcentrationsbeassayedandthatthedoseshouldbeadjustedif

necessary.

Rifampicin:Riskofdecreaseofdiltiazemplasmalevelsafterinitiatingtherapywithrifampicin:Thepatientshouldbe

carefullymonitoredwheninitiatingordiscontinuingrifampicintreatment.

Anti-H2agents(cimetidine,ranitidine):Increaseinplasmadiltiazemconcentrations.

Patientscurrentlyreceivingdiltiazemtherapyshouldbecarefullymonitoredwheninitiatingordiscontinuingtherapy

withanti-H2agents.Anadjustmentindiltiazemdailydosemaybenecessary.

Ciclosporin:Increaseincirculatingcyclosporinlevels:

Itisrecommendedthatthecyclosporindosebereduced,renalfunctionbemonitored,circulatingcyclosporinlevelsbe

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 3

Benzodiazepines(midazolam,triazolam):Diltiazemsignificantlyincreasesplasmaconcentrationsofmidazolamand

triazolamandprolongstheirhalf-life.Specialcareshouldbetakenwhenprescribingshort-actingbenzodiazepines

metabolizedbytheCYP3A4pathwayinpatientsusingdiltiazem.

Corticosteroids(methylprednisolone):Inhibitionofmethylprednisolonemetabolism(CYP3A4)andinhibitionof

Pglycoprotein:Thepatientshouldbemonitoredwheninitiatingmethylprednisolonetreatment.Anadjustmentinthe

doseofmethylprednisolonemaybenecessary.

Clopidogrel:Aliteraturereporthassuggestedaninteractionbetweenclopidogrelandcalciumchannelblockers

(includingdiltiazem)whichmayreducetheeffectivenessofclopidogrel.Howevertheclinicalsignificanceofthis

interactionisunknown.

Generalinformationtobetakenintoaccount:

Duetothepotentialforadditiveeffects,cautionandcarefultitrationarenecessaryinpatientsreceivingdiltiazem

concomitantlywithotheragentsknowntoaffectcardiaccontractilityand/orconduction.

DiltiazemismetabolizedbyCYP3A4.Amoderate(lessthan2fold)increaseofdiltiazemplasmaconcentrationin

casesofcoadministrationwithastrongerCYP3A4inhibitorhasbeendocumented.DiltiazemisalsoaCYP3A4

isoforminhibitor.CoadministrationwithotherCYP3A4substratesmayresultinanincreaseinplasmaconcentration

ofeithercoadministereddrug.CoadministrationofdiltiazemwithaCYP3A4inducermayresultinadecreaseof

diltiazemplasmaconcentrations.

Simultaneousadministrationwithenzymeinducerssuchasrifampicinandphenobarbitalmayleadtoreducedactivity

ofdiltiazem.

Antihypertensives:Diltiazemhydrochlorideshouldonlybeadministeredwithgreatcaretopatientsreceiving

concurrenttreatmentwithantihypertensivesorotherhypotensiveagentsincludinghalogenatedanaestheticsordrugs

withmoderateproteinbinding.

Diltiazemhydrochloridewillnotprotectagainsteffectsofwithdrawalofß-adrenoceptorblockingagents,northe

reboundeffectsseenwithvariousantihypertensives.

Theremaybeanadditiveeffectwhendiltiazemisusedwithdrugswhichmayinducebradycardiaorwithother

antihypertensives.

4.6Fertility,pregnancyandlactation

Thereisverylimiteddatafromtheuseofdiltiazeminpregnantpatients.Diltiazemhasbeenshowntohave

reproductivetoxicityincertainanimalspecies(rat,mice,rabbit).Diltiazemshouldnotbeusedduringpregnancy,as

wellasinwomenofchildbearingpotentialnotusingeffectivecontraception(seesection4.3).

Diltiazemisexcretedinbreastmilkatlowconcentrations.Breastfeedingwhiletakingthisdrugshouldbeavoided.If

useofdiltiazemisconsideredmedicallyessential,analternativemethodofinfantfeedingshouldbeinstituted.

4.7Effectsonabilitytodriveandusemachines

Onthebasisofreportedadversedrugreactions,i.e.dizziness(common),malaise(common),theabilitytodriveand

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 4

4.8Undesirableeffects

ThefollowingCIOMSfrequencyratingisused,whenapplicable:Verycommon(1/10);common(1/100to<1/10);

uncommon(1/1,000to1/100);rare(1/10,000to1/1,000);veryrare(1/10,000);notknown(cannotbeestimated

fromtheavailabledata).

Withineachfrequencygrouping,adverseeventsarepresentedinorderofdecreasingseriousness.

Verycommon Common Uncommon Rare Notknown

Bloodand

lymphatic

systemdisorders Thrombocytopenia,

lymphadenopathy,

eosinophilia

Psychiatric

disorders Nervousness,

insomnia Hallucinations,

moodchanges

(including

depression),

personality

change

Nervoussystem

disorders Headache,

dizziness Extrapyramidal

syndrome,gait

abnormality,

syncope,amnesia,

paraesthesia,

somnolence,

tremor,

myasthenia

gravisaggravated

Cardiac

disorders Atrioventricular

block(maybeof

first,secondor

thirddegree;

bundlebranch

blockmay

occur),

palpitations Bradycardia Sinoatrialblock,

congestiveheart

failure,

arrhythmia,

angina

Vascular

disorders Flushing Orthostatic

hypotension Vasculitis

(including

leukocytoclastic

vasculitis),

hypotension

Gastrointestinal

disorders Constipation,

dyspepsia,

gastric

pain,nausea Vomiting,

diarrhoea Drymouth Gingival

hyperplasia,

gingivitis

Hepatobiliary

disorders Hepatitis

Skinand

subcutaneous

tissue

disorders Erythema Urticaria Allergicskin

reactions,

photosensitivity

(including

lichenoid

keratosisatsun

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 5

skinareas),

angioneurotic

oedema,rash,

erythema

multiforme

(including

Steven-Johnson's

syndromeand

toxic

epidermal

necrolysis),

sweating,

exfoliative

dermatitis,acute

generalized

exanthematous

pustulosis,

occasionally

desquamative

erythema

withorwithout

fever,

petechiae,pruritus

Reproductive

system

andbreast

disorders Gynecomastia,

sexual

difficulties

General

disorders

and

administration

siteconditions Peripheral

oedema Oedema,

asthenia,

malaise

Eyedisorders Amblyopia,eye

irritation

Investigations Hepatic

enzymes

increase(AST,

ALT,LDH,

increase) CKelevation,

weight

increase,

bleedingtime

prolonged

Respiratory,

thoracicand

mediastinal

disorders Dyspnoea,

epistaxis,nasal

congestion

Metabolismand

nutrition

disorders Anorexia,

hyperglycaemia

Renaland

urinary

disorders Nocturia,polyuria

Musculoskeletal

and

connectivetissue

disorders Osteoarticular

pain,

musclepain,

muscle

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 6

4.9Overdose

Theclinicaleffectsofacuteoverdosecaninvolvepronouncedhypotensionpossiblyleadingtocollapse,sinus

bradycardiawithorwithoutisorhythmicdissociation,andatrioventricularconductiondisturbances.

Experienceofoverdosageinmanislimitedbutcasesofspontaneousrecoveryhavebeenreported.However,itis

recommendedthatpatientswithsuspectedoverdose,shouldbeplacedunderobservationinacoronarycareunitwith

facilitiesavailablefortreatmentofanypossiblehypotensionandconductiondisturbancesthatmayoccur.

Mostpatientssufferingfromoverdosageofdiltiazembecomehypotensivewithin8hoursofingestion.With

bradycardiaandfirsttothirddegreeatrioventricularblockalsodevelopingcardiacarrestmayensue.Hyperglycaemiais

alsoarecognisedcomplication.Theeliminationhalf-lifeofdiltiazemafteroverdosageisestimatedtobeabout5.5-

10.2hours.Ifapatientpresentsearlyafteroverdose,gastriclavageshouldbeperformedandactivatedcharcoal

administeredtoreducediltiazemabsorption.

Hypotensionshouldbecorrectedwithplasmaexpanders,intravenouscalciumgluconateandionotropicagents

(dopamine,dobutamine,isoprenaline),symptomaticbradycardiaandhighgradeAVblockmayrespondtoatropine,

isoprenalineoroccasionallycardiacpacingwhichmaybeusefulifcardiacstandstilloccurs.

5PHARMACOLOGICALPROPERTIES

5.1Pharmacodynamicproperties

Diltiazemisacalciumchannelblockingagent.Theprecisemechanismofaction,whichisdosedependent,isunknown,

butcalciumchannelblockersactpredominantlyatspecificvoltage-sensitiveion-selectivechannels,"slowcalcium

channels"ofcardiacandsmoothmusclecellswhoseexcitation-contractioncouplingrequiresaninwarddisplacement

ofcalcium.

Calciumchannelblockersarevasodilatorswhoseantihypertensiveeffectsareassociatedwithdecreasesinperipheral

resistanceleadingtoadropinbloodpressure.

Theantianginaleffectsofdiltiazemhydrochlorideareprobablyrelatedtoitscoronaryarteryvasodilatingeffectandto

itshaemodynamiceffects.

Theformulationispresentedasasustainedreleasepreparationfortwicedailyadministration.

5.2Pharmacokineticproperties

a)GeneralCharacteristics

Absorption:Capsulesseemtohaveasimilarbioavailabilitytotablets(30-40%),withpeakconcentrationsforthe

sustainedreleaseproductafter8-11hourscomparedwith1-2hoursaftertheconventionalreleaseproduct.The

relativelylowbioavailabilityisduetofirstpassmetabolisminthelivertoanactivemetabolite.

Distribution:Diltiazemhydrochlorideislipophilicandhasahighvolumeofdistribution.

Typicalstudyresultsareintherangeof3-8litres/kg.Proteinbindingisabout80%andisnotconcentrationdependent

atlevelslikelytobefoundclinically.Proteinbindingdoesnotappeartobeinfluencedbyphenylbutazone,warfarin,

propanolol,salicylicacidordigoxin.

Metabolism:Diltiazemhydrochlorideisextensivelymetabolisedintheliver.N-monodesmethyldiltiazemisthe

Earand

labyrinth

disorders Tinnitus Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 7

Theefficacyofthemetabolites,desacetyldiltiazemandN-monodesmethyldiltiazemis25-50%andabout20%

respectivelyofthatofdiltiazem.Inliverfunctiondisordersdelayedmetabolismintheliverislikely.Thesemetabolites

areconvertedtoconjugates,generallytheglucuronideorthesulphate.

Elimination:Diltiazemisexcretedintheformofitsmetabolites(about35%)andinthenon-metabolisedform(about2-

4%)viathekidneyswhileabout60%isexcretedviathefaeces.Theaverageeliminationhalflifeperiodfordiltiazemis

6-8hoursbutmayvarybetween2and11hours.Althoughtheeliminationhalflifeperiodisnotchangedafterrepeated

oraladministration,diltiazemandalsothedesacetylmetaboliteshowaslightaccumulationintheplasma.

b)CharacteristicsinPatients

Decreasedfirst-passmetabolismintheelderlytendstoresultinincreasedplasmaconcentrationsofcalciumantagonists

butnomajorchangeshavebeenfoundwithdiltiazem.Renalimpairmentdidnotcausesignificantchangesindiltiazem

pharmacokinetics.Plasmaconcentrationsofdiltiazemalsotendtobehigherinhepaticcirrhosisduetoimpaired

oxidativemetabolism.

5.3Preclinicalsafetydata

Chronictoxicitystudiesinratsrevealednoremarkablechangesatoraldosesupto125mg/kg/dayalthoughtherewasa

60%mortalityatthisdose.Indogschronicallytreatedwithoraldosesof20mg/kg/day,transientrisesinSGPTwere

observed.Embryotoxicityhasbeenreportedinmice,ratsandrabbitsfollowingi.p.administrationofdiltiazem.Main

typesofmalformationsincludedlimbandtaildefectswithasmallnumberofvertebralandribdeformitiesalsonoted.

6PHARMACEUTICALPARTICULARS

6.1Listofexcipients

Fumaricacid

Talc

Povidone

Sucroseandmaizestarch

AmmoniomethacrylatecopolymerTypeA

AmmoniomethacrylatecopolymerTypeB

Gelatin

Titaniumdioxide(E171)

Blackironoxide(E172)

Shellac

PropyleneGlycol(E1520)

Purifieldwater

6.2Incompatibilities

NotApplicable.

6.3Shelflife

Theshelflifeexpirydateforthisproductshallbethedateshownontheblisterandouterpackageoftheproductonthe

marketinthecountryoforigin.

6.4Specialprecautionsforstorage

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 8

6.5Natureandcontentsofcontainer

PVC/PVDCBlisterPack:containing30capsules.

6.6Specialprecautionsfordisposalofausedmedicinalproductorwastematerialsderivedfrom

suchmedicinalproductandotherhandlingoftheproduct

Nospecialrequirements

7PARALLELPRODUCTAUTHORISATIONHOLDER

LTTPharmaLimited

Unit18,OxleasowRoad

EastMoonMoat

Redditch

WorcestershireB980RE

UnitedKingdom

8PARALLELPRODUCTAUTHORISATIONNUMBER

PPA1562/26/1

9DATEOFFIRSTAUTHORISATION/RENEWALOFTHEAUTHORISATION

Dateoffirstauthorisation:12 th

November2010

10DATEOFREVISIONOFTHETEXT

Irish Medicines Board

______________________________________________________________________________________________________________________

Date Printed 17/04/2012 CRN 2111390 page number: 9