Diltahexal

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Active ingredient:
Diltiazem hydrochloride 60 mg;  
Available from:
Novartis New Zealand Ltd
INN (International Name):
Diltiazem hydrochloride 60 mg
Dosage:
60 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Diltiazem hydrochloride 60 mg   Excipient: Colloidal silicon dioxide Hydrogenated castor oil Hypromellose Lactose monohydrate Macrogol 6000 Magnesium stearate Microcrystalline cellulose   Povidone Sodium starch glycolate Stearic acid Titanium dioxide
Units in package:
Blister pack, PVC/PE/PVDC & aluminium foil, 100 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Lusochimica SpA
Product summary:
Package - Contents - Shelf Life: Blister pack, PVC/PE/PVDC & aluminium foil - 100 tablets - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-6011
Authorization date:
1997-07-22

NEWZEALANDDATASHEET

Diltahexal

DiltiazemHydrochloridePh Eur,filmcoatedtablet, 60mg

Presentation

White,9mm,film-coatedtablets, scoredonone side.Each tabletcontainsdiltiazemhydrochloride60

mg.Thisproduct isnotable todeliver allapproveddose regimes.Do nothalve tablet.

Uses

Actions

Pharmacotherapeuticgroup

C08DB01-Selective calciumchannelblockerswithmainlyvascular effects, benzothiazepine

derivatives, diltiazem.

Mechanism ofaction

Diltiazem, abenzothiazepine type calciumantagonist, inhibitscalciumionentryinto smoothmuscle

cellsbyblockade ofslowcalciumchannels.Diltiazemactsasapotentcoronaryvasodilator and also

hasamoderateeffect on peripheralcirculation.Diltiazemmayalsoprolong AVnodalconduction.

Pharmacodynamiceffects

Thetherapeuticeffectsachievedwith diltiazemare believed toberelatedtoitsabilitytoinhibit the

influxofcalciumionsduring membranedepolarisationofcardiacand vascular smoothmuscle.

Diltiazemproducesitsantihypertensiveeffectsbyprimarilybyrelaxationofvascular smoothmuscle

and theresultantdecreasein peripheralvascular resistance.Themagnitudeofbloodpressureis

related tothedegreeofhypertension;thushypertensive individualsexperience anantihypertensive

effect, whereasthereisonlya modest fallinbloodpressure in normotensives.

Incommonwithsomeothercalciumantagonists, diltiazemdecreasessinoatrialandatrioventricular

conductioninisolated tissuesandhasanegativeinotropiceffect isisolated preparations.Intheintact

animal, prolongation oftheatrial-His(A-H)intervalcanbeseen athigherdoses.

Inanimalmodels, diltiazeminterfereswiththeslowinward (depolarising) currentinexcitable tissue. It

causesexcitation-contractionuncouplinginvariousmyocardialtissueswithout changesin the

configurationofthe actionpotential.Diltiazemproducesrelaxation ofcoronaryvascular smooth

muscle anddilationofbothlargeand smallcoronaryarteriesatdruglevelswhichcause little orno

negativeinotropiceffect.Theresultantincrease in coronaryblood flow(epicardialand

subendocardial)occur inischaemicand nonischaemicmodelsandare accompaniedbydose

dependentdecreasesin systemicblood pressureanddecreasesin peripheralresistance.

Inmandiltiazemhydrochloridepreventsspontaneousandergometrineprovokedcoronaryartery

spasm. Itcausesadecrease inperipheralvascular resistance and amodest fallinbloodpressure

and,inexercise tolerance studiesinpatientswith ischaemicheart disease, reducesthe heart rate-

bloodpressure product for anygivenworkload.Studiestodate,primarilyin patientswithgood

ventricular function, have notrevealedevidenceofanegative inotropiceffect; cardiacoutput,ejection

fractionandleft ventricularenddiastolicpressure havenotbeen affected. Increasedheart rate has

howeverbeen reportedinoccasionalpatientswith pre-existing impairment ofthe ventricular function.

There isverylittledataontheinteractionofdiltiazemhydrochlorideandbeta-blockersin patientswith

poorventricular function. Restingheart rateisusuallyreducedbydiltiazem.

Diltiazemproducesantihypertensiveeffectsbothinthesupine andstandingpositions. Postural

hypotensionisinfrequentlynoted uponsuddenlyassuminganuprightposition. No reflextachycardia

isassociatedwiththechronicantihypertensive effects. Diltiazemdecreasesvascular resistance,

increasescardiacoutput(byincreasing stroke volume)andproducesaslightdecrease orno change

in heart rate.During dynamicexercise,increasesin diastolicpressureareinhibitedwhile maximum

achievablesystolicpressure isusuallyreduced.Heartrateatmaximumexercisedoesnotchangeor

isslightlyreduced. Chronictherapywithdiltiazemproducesnochangeor an increase inplasma

catecholamines. Noincreasesactivityofthe renin-angiotension-aldosteroneaxishasbeenobserved.

Diltiazemantagonisesthe renaland peripheraleffectsofangiotensionII.Hypertensiveanimalmodels

respondto diltiazemwithreductionsinbloodpressureandincreased urinaryoutputand natriuresis

withouta changeinurinarysodium/potassiumratio.

Evaluationofglucoseandlipidhomeostasisindiabeticandnon-diabeticsubjectstreatedwith calcium

antagonistsindicatesthatdiltiazemdoesnotaffect energymetabolismin themajorityofindividuals.

Clinicalstudies

Intravenousdiltiazemhydrochloridein dosesof20mg prolongsatrial-Hisconductiontime and

atrioventricular nodefunctionaland effective refractoryperiodsbyapproximately20%. In astudy

involvingsingleoraldosesofdiltiazem300 mg in sixnormalvolunteers, theaveragemaximumPR

prolongationwas14%withnoinstancesofgreaterthan first degreeatrioventricular block. Diltiazem

associatedprolongationoftheatrial-Hisintervalisnotmore pronouncedinpatientswithfirst degree

heart block. Inpatientswithsicksinussyndrome,diltiazemsignificantlyprolongssinuscyclelength

(upto50%in some cases).

ChronicoraladministrationofDiltiazemin dosesofupto240 mg/dayhasresultedin smallincreases

inPKintervalbuthasnot usuallyproduced abnormalprolongation.Therewere,however, three

instancesofsecond degreeatrioventricular blockand oneinstanceofthirddegreeatrioventricular

blockinagroupof959 chronicallytreated patients.

Therapeutics

Angina due tocoronaryarteryspasm(vasospasticangina)

Diltiazemhasbeen shown to bea potent dilator ofcoronaryarteriesboth epicardialand

subendocardial.and itinhibitsspontaneousandergometrineinduced coronaryarteryspasm.

Exertionalangina

Diltiazemhasbeen shown to produce increasesin exercise tolerance,probablyduetoitsabilityto

reduce myocardialoxygendemand andincrease oxygensupply. Thisisaccomplishedthrough

reductionsin heart rate, systemicblood pressureatsubmaximaland maximalexercise workloads

anddilationofcoronaryarteries.

Pharmacokinetics

Absorption

Diltiazemisalmost completelyabsorbedafter oraladministration butfirst passmetabolismlimitsits

systemicavailabilitytoabout50%. Although detectable inplasma between30to60minutesafter

administration,peaklevelsare normallyachieved2 to4 hoursafter administrationofthe 60 mg

tablets.

Distribution

Diltiazemisdistributed tothe liver, kidney, lung, spleen, heartandbrainwithtissueconcentration

decreasing in thatorder. Plasma protein binding accountsfor 77 to86%ofplasma diltiazem, 35 to

40% beingbound toalbumin and the rest toalpha-glycoprotein.Competitiveligand bindingstudies

have also shown diltiazembinding isnotalteredbytherapeuticconcentrationsofdigoxin,

hydrochlorothiazide,phenylbutazone,propranolol,salicylicacidorwarfarin.Diltiazemhydrochlorideis

excreted in breast milk.

Biotransformation

Diltiazemisextensivelymetabolised in the liver bydeacetylation,N-demethylationand O-

demethylationsuch thatonly0.1 to4% ofunchangeddiltiazemappearsin the urine.Five metabolites

have beenidentified.Desacetyldiltiazemisnormallypresentin plasma at levelsof10to 20%ofthe

parent medicineandis25to 50%aspotentavasodilator asdiltiazem. Some studieshave, however,

shown that thismetabolitecanaccumulateduring multiple oraldosing and the plasma concentration

mayexceedthatoftheparent medicine.Anothermetabolite,N-mono-demethyl-diltiazemmaybe

about 20% aspotent astheparentdrug. Theother metabolitesare devoid ofpharmacologicalactivity.

Elimination

Studiesin ratshave shownthatafter administrationof14C-diltiazem, greater than90% ofthe 14C

labelcan beremovedfromurineand faecesin72hours. Excretionofdiltiazemmetabolitesinthe

faecesseemstobethe main routeofelimination sincemore than 60%ofthe doseisexcretedinto the

bile in 24 hoursand65%intothe faecesin72hours. There isextensiveenterohepaticcirculation.

Theplasma eliminationhalf-life following single ormultipledrugadministrationisapproximately4 to 6

hours.

Correlationwiththerapeuticactivity

Therapeuticbloodlevelsofdiltiazemappear tobein the range or50 to200 nanogram/ml.Plasma

levelsabove50ng/mlare achievedbetween1to 1.5 hoursandare maintained for approximately8

hoursafter administrationofthe 60 mg tablets.There isadeparture fromdose linearitywhensingle

dosesabove 60mg are given; a120 mg dose gavebloodlevelsthreetimesthatofthe 60mg dose.

Desacetyldiltiazemisalsopresentin theplasma at levelsof10to 20% oftheparentdrugand is25to

50% aspotenta coronaryvasodilator asdiltiazem.

Specialpatientconsiderations

Patientswithhepaticor renalimpairment

Littleinformationisavailable astotheeffect ofage,renalor hepaticdysfunctionon the

pharmacokineticprofile,other thanthat the more pronouncedanti-hypertensive effect seenin the

elderlymaybedueto adecreasedclearance.

Indications

Angina pectorisdue to coronaryarteryspasmand chronicstableangina.

Dosageandadministration

Thisproduct isnotable todeliver allapproved dose regimes.Do not halve tablet.

Initially30mgthree tofourtimesdailyincreasing to240 mg dailyin divideddoses. Themaximum

recommended dose is360mg daily.

Usein theelderly

Pharmacokineticsofdiltiazemin elderlypatientshasnotbeenfullyelucidated.Preliminaryresultsin

elderlypatients(over 65yearsold) suggest thata lowerdosage mightberequiredin thisagegroup.

Impairedhepatic orrenalfunction

There are fewavailabledata concerningdosage requirementsin patientswith impairedrenalor

hepaticfunction.Diltiazemshould beusedwith caution inpatientswith hepaticorrenalimpairment. If

diltiazemmust be usedinthese patients, thedosage should be carefullyandgraduallyadjusted

dependingonpatient tolerabilityandresponses.

Concomitantuse withothercardiovascularagents

Sublingualglyceryltrinitratemaybetakenasrequired to abortacuteanginalattacksduringdiltiazem

therapy. Diltiazemmaybesafelyco-administeredwithshort-andlong-actingnitrates.

Contraindications

Known hypersensitivitytodiltiazemor to anyofthe inactiveingredientslistedinFurther information.

Sick-sinussyndrome except in thepresenceofafunctioningventricular pace-maker; sinoatrial(SA)

nodedisorders;secondor third degreeatrioventricularblockexcept inthepresence ofafunctioning

ventricular pacemaker;hypotension(<90mmHg systolic);severe congestiveheart failure;severe

bradycardia(below40bpm);left ventricular failurewithpulmonarycongestion;patientswithacute

myocardialinfarctionandpulmonarycongestiondocumentedbyX-rayonadmission;idiosyncrasyor

hypertensiontodiltiazem;concomitant useofdantroleneinfusion(refer toInteractions);Pregnancy.

Warningsandprecautions

Warnings

Cardiac conduction

Closeobservationisnecessaryinpatientswithreduced leftventricular function,bradycardiaorwith a

first degreeAVblock.DiltiazemprolongsA-Vnoderefractoryperiodswithout significantlyprolonging

sinusnoderecoverytime,except inpatientswith sicksinussyndrome.Thiseffectmayrarelyresultin

abnormallyslow heart rates(particularlyin patientswith sicksinussyndrome) orprolongationofthe

PR intervalor evensecond-or third-degree A-Vblock(6of1,243patients, or0.48%). Concomitant

use ofdiltiazemwithbeta-blockersor digitalismayresultinadditiveeffectsoncardiacconduction.A

patientwith Prinzmetal'sangina developedperiodsofasystole (2 to 5seconds)after a single dose of

60mg ofdiltiazemhydrochloride.

Congestive heartfailure

Althoughdiltiazemhasanegative inotropiceffect inisolatedanimaltissuepreparations,

haemodynamicstudiesinhumanswith normalventricular function have not shownareductionin

cardiacindexnorconsistent negativeeffectsoncontractility(dp/dt).Anacutestudyoforaldiltiazemin

patientswithimpairedventricular function(ejectionfraction24%+/-6%)showed improvement in

indicesofventricular functionwithoutsignificantdecrease incontractilefunction(dp/dt).Experience

withtheuse ofdiltiazemincombinationwith beta-blockersin patientswithimpairedventricular

functionislimited.Cautionshould beexercisedwhenusingthiscombination.

Hypotension

Arteriolardilationwith consequentialdecreasesin blood pressure isassociatedwithdiltiazemtherapy

andmayoccasionallyresult in symptomatichypotension.

Acute hepaticinjury

Mild elevationsoftransaminaseswith andwithout concomitant elevation in alkaline phosphatase and

bilirubinhavebeen observed inclinicalstudies.Suchelevationswereusuallytransientand frequently

resolvedevenwithcontinueddiltiazemtreatment. In rare instances, significant elevationsinenzymes

such asalkalinephosphatase,LDH,SGOT, SGPT, and other phenomena consistentwithacute

hepaticinjuryhave beennoted. These reactionstended tooccurearlyafter therapyinitiation (1 to 8

weeks)and havebeen reversible upondiscontinuation ofdrug therapy. Therelationship to diltiazem

isuncertainin some cases, butprobable in some (refertoAdverse effects).

Concomitantadministrationwithbeta-blockers

Controlledanduncontrolledstudiessuggestthattheconcomitant use ofdiltiazemandbeta-blockers

ordigitalisglycosidesisusuallywelltolerated.However, diltiazemmaycausemarkedprolongationof

atrioventricular conduction in asmallnumberofpatients, andcautionisadvised ifcombination

therapyisconsidereddueto theriskofbradycardia. Such acombinationshouldnotbeusedin

patientswithdepressedleft ventricular function and conductionsystemdisease(refer toInteractions).

Abruptwithdrawal

Thesuddenwithdrawalofdiltiazemhasbeen associatedwithsevereangina.

Precautions

Impairedhepatic orrenalfunction

Plasma diltiazemconcentrationscan beincreasedin patientswithrenalor hepaticinsufficiency.

Diltiazemisextensivelymetabolised bythe liver, metabolitesbeingeliminatedbythekidneysand in

bile.Diltiazemshouldbeusedwithcautionandatreduceddosagein patientswithimpairedrenalor

hepaticfunction.Liver functiontestsshouldbemonitoredduring prolongeduse asveryrare

transaminase elevationshavebeen noted.Animalsubacutetoxicityandchronictoxicitystudiesin

dogsandratsindicated hepaticdamage occurredathighdosages. Such damage wasreversible

whenthedrugwasdiscontinued.

Usein diabetics

Diltiazemshouldbeusedwithcautionin patientssuffering fromdiabetes.Incommonwithother

calciumchannelblockers,diltiazeminfluencesinsulinsecretionanditsperipheralaction byinhibiting

calciuminfluxinto cells. Inone study,increasesinfastingandpeakglucose levelswereobserved

after 2to6months' diltiazemadministration.

Usewithamiodarone

Amiodaroneshouldbeusedwith cautionwithdiltiazemparticularlyifthereissuspicion ofunderlying

dysfunction ofthe sinusnode, suchasbradycardia orsicksinussyndrome orifthere ispartialA-V

block(refer toInteractions).

Concomitantuse withdigoxin

Diltiazemhasbeen shown to increase serumdigoxinconcentrationsand to modifyits

pharmacokinetics(refer toInteractions). Patientswithplasma digoxinlevelsin theupper therapeutic

range(1.5to 2.5 ng/ml)maydevelop toxicplasma concentrationsandsideeffects.Thecombination

ofdiltiazemwithdigoxinordigitalisglycosidesmayhaveadditiveeffectsin prolonging AVconduction.

Therefore, digoxin plasma concentrationsshould be controlled 6to 8daysafter starting these drug

combinations,atwhich time new steadystateconditionsdevelopandthedigoxindose canbe

reducedifthereisevidenceoftoxicity.

Longterm use

Datato support long-termuse ofdiltiazemtreatment longer thanoneyearwithdoseshigher than240

mg/dayarelimited. Therefore long-termtreatment withdosesexceeding240 mg/dayisnot

recommended.

Usein theelderly

Administrationofdiltiazemtoelderlypatients65yearsofage orolder requirescaution. Plasma

diltiazemconcentrationscan beincreased in the elderly.Theincidence ofadversereactionsis

approximately13% higher in thisgroup. Those adverse reactionswhich occur more frequentlyinclude

peripheraloedema,bradycardia,palpitation,dizziness, rash and polyuria.Therefore, particular carein

titrationisadvisable.

Paediatricuse

Safetyandeffectivenessinchildrenhave notbeenestablished.

Lactoseintolerance

Sincethismedicinalproduct containslactose,patientswithrare hereditaryproblemsofgalactose

intolerance,theLapplactase deficiencyor glucose-galactose malabsorptionshould nottake this

medicine.

Pregnancyand lactation

Usein pregnancy

Assigned CategoryCbythe AustralianDrugEvaluation Committee.Thiscategoryincludesmedicines

which,owingto theirpharmacologicaleffects, have causedor maybesuspectedofcausing,harmful

effectsonthe humanfoetusor neonatewithout causing malformations. These effectsmaybe

reversible.Accompanyingtextsshould beconsultedfor further details.

Reproduction studieshavebeenconductedin mice,ratsand rabbits. Administrationofhighdoses

hasresultedinembryoandfoetallethality. These doses, in some studies,havebeenreportedto

cause skeletalabnormalities. Intheperinatal/postnatalstudiestherewassome reduction in early

individualpupweightsandsurvivalrates. Therewasan increasedincidenceofstillbirthsathigh

doses.

There are nowellcontrolled studiesin pregnantwomen.Incommonwithother calciumchannel

blockers, diltiazemhasthepotentialto produce foetalhypoxiaassociatedwithmaternalhypotension.

Accordingly, diltiazemshould notbe used in pregnantwomenunlessthe potentialbenefit outweighs

therisktothe foetus.

Usein lactation

Residualdiltiazemmaybepresentin breast milkatlevelscorresponding to approximately0.9% ofthe

maternaldose.Diltiazemisconsidered unlikelyto beproblematicalinbreastfeeding.

Effects on abilitytodriveand usemachines

Thismedicineispresumedtobesafe orunlikelytoproduce an effect.

Other

Preclinicalsafetydata

Toxicology

TheoralLD50valuesin mice andratsrangedfrom415 to740 mg/kg andfrom560 to810 mg/kg,

respectively. TheintravenousLD50valuesinthese specieswere60and38mg/kg,respectively. The

oralLD50indogsisconsidered tobeinexcessof50mg/kg,whilelethalitywasseenin monkeysat

360 mg/kg.Thetoxicdosein manisunknown, butblood levelsin excessof800 ng/mlhavenotbeen

associatedwith toxicity.

Adverseeffects

Seriousadverse reactionshave been rare in studiescarriedout to date,butit shouldberecognised

thatpatientswithimpairedventricular functionand cardiacconductionabnormalitieshave usually

beenexcludedfromthese studies.

Common reactions

Inclinicaltrialsofdiltiazemin anginalpatients, themost commonevents(i.e. greater than1%)were

oedema (2.4%), headache(2.1%), nausea(1.9%), atrioventricular block(1.5%), dizziness(1.5%),

rash (1.3%), asthenia (1.2%), urticaria and lightheadedness.

Uncommon reactions

Thefollowingeventswere reported infrequently(lessthan1%).

Cardiovascular

Angina,arrhythmia,first degree atrioventricular block,second-or third-degreeatrioventricular block,

bradycardia, bundlebranchblock, congestiveheart failure,ECGabnormalities,flushing,hypotension,

palpitations, syncope,tachycardia,ventricular extrasystoles.Atrioventricular blockisanuncommon

but potentiallyseriousadverse effect ofdiltiazemtreatment andtheriskisincreasedbyconcurrent

use ofabeta-blocker.

Nervous system

Abnormaldreams, amnesia,depression,gait abnormality,hallucinations, insomnia,nervousness,

paraesthesia,personalitychange,somnolence, tinnitus, tremor.

Gastrointestinal

Anorexia,constipation,diarrhoea,drymouth,dysgeusia,dyspepsia,thirst,vomiting,weight increase,

mild elevationsofSGOT, SGPT,AST, ALT,LDH,andalkaline phosphatase.Inrare cases, clinical

hepatitishasbeenreported, reversible upondiscontinuation ofdiltiazem.

Dermatological

Petechiae,photosensitivity,pruritus,urticaria.

Other

Amblyopia,creatinephosphokinase elevation, dyspnoea, epistaxis, eyeirritation,hyperglycaemia,

sexualdifficulties,nasalcongestion,nocturia,muscle cramps,osteoarticular pain, impotence,dry

mouth,polyuria,hyperuricaemia.

Post-marketingsurveillance

Thefollowingpost-marketingeventshave beenreported infrequentlyinpatientsreceivingdiltiazem:

alopecia,gynaecomastia,vasculitis, musculo-cutaneousreactionssuchassimple erythema or

occasionallydesquamativeerythema with orwithout fever, angioneuroticoedema,symptomsof

vasodilation(suchasflushing,lowerlimb oedema,sweating), erythemamultiforme (includingrare

casesofStevens-Johnsonsyndrome), acutegeneralisedexanthematouspustular dermatitis, sino-

atrialblock, orthostatichypotension, malaise,gastricpain,purpura,exfoliative dermatitis,

extrapyramidalsymptoms, gingivalhyperplasia,haemolyticanaemia,increasedbleeding time,

leucopenia,retinopathy, agranulocytosisand thrombocytopenia.Bradycardiaandheart block(sino-

atrialand/oratrioventricular)have also beennotedashave muscular (including myalgia) effectsand

ocular (includingabnormalvision)changes.Veryrarecasesoftoxicepidermalnecrolysishave been

reported.

Inaddition,eventssuch asmyocardialinfarctionhavebeenobservedwhich arenotreadily

distinguishablefromthe naturalhistoryofthedisease ofthese patients. Anumberofwell-documented

casesofrash,characterisedasleucocytoclasticvasculitis, havebeenreported.However, adefinitive

cause and effect relationship between these eventsand diltiazemtherapyisyettobeestablished.

Interactions

Medicinesand otherpharmacologicallyactivesubstances

Dueto the potentialfor additiveeffects, cautionandcarefultitration arenecessaryinpatients

receiving diltiazemconcomitantlywith otheragentsknown toaffect cardiaccontractilityand/or

conduction.

Aswith alldrugs, care should be exercisedwhentreatingpatientswithmultiplemedications. Diltiazem

undergoesbiotransformation bycytochrome P450 mixedfunction oxidase.Co-administrationof

diltiazemwithother agentsthat followthesame routeofbiotransformationmayresult in the

competitive inhibition orinductionofmetabolism. Thismayleadto an increasedriskofadverse

reactions.

Alpha-adrenoceptorantagonists

Concomitant treatment withalpha-blockersmayproduce oraggravatehypotension.Thecombination

ofdiltiazemwithan alpha-blocker shouldonlybeconsideredwith the strict monitoringofblood

pressure duetotheriskofincreasedantihypertensiveeffects.

Amiodarone

Sinusarrest andalife-threateninglow cardiacoutputstate developedwhenamiodaronewasadded

toa regimenofdiltiazemand adiuretic. It hasbeen suggestedthatdiltiazemand amiodaronehave

additiveadverse effectsonsinusnodefunctionandonmyocardialcontractility(refer toWarningsand

precautions).

Anaestheticagents

Additivehaemodynamicdepressiveeffectsare foundwhencalciumchannelblockersare combined

withinhalationanaestheticagentssuch ashalothane,isofluraneorenflurane.These effectsare

related bothto the anaestheticconcentrationandtothe doseofthe calciumchannelblocker.

Depression ofcardiaccontractility, conductivityandautomaticity, aswellasvascular dilatation

associatedwith anaestheticsmaybepotentiated bycalciumchannelblockers.

Asinglecase hasbeen reported ofcardiacarrhythmia involvingsinusarrestandimpairedAV

conductionafter administrationofenflurane anddiltiazemtogether.

Prior to generalanaesthesia,the anaesthetist must beinformedofongoing diltiazemtreatment.

Antiarrhythmic agents

Sincediltiazemhasantiarrhythmicproperties,it’sconcomitant usewith otherantiarrhythmicagentsis

not recommended.Such combinationshouldonlybeusedundercloseclinicaland ECGmonitoring.

Beta-blockers

Thecombinationofdiltiazemwithbeta-blockersmayproduce apositive clinicalresponse in patients

withangina pectoris. Care isrequired,however, sinceAVconductionmaybeprolonged leading to

seriousdeleteriouseffects(refer toWarningsandprecautions).

Controlledanduncontrolledstudiessuggestthatconcomitant use ofdiltiazemand beta-blockersor

digitalisglycosidesisusuallywelltolerated,butavailable dataare notsufficient topredict theeffects

ofconcomitant treatment inpatientswithleftventriculardysfunctionor cardiacconduction

abnormalities.

Administrationofdiltiazemconcomitantlywithpropranololin five normalvolunteersresultedin

increasedpropranolollevelsin allsubjectsandbioavailabilityofpropranololwasincreasedby

approximately50%. Ifcombinationtherapyisinitiatedor withdrawninconjunctionwithpropranolol, an

adjustment in the propranololdose maybewarranted.

Incontrast,thereappearsto benoeffect on thepharmacokineticsofatenolol,a renallycleareddrug.

Inview ofthe knownpharmacodynamicinteractionsbetweentheseclassesofdrugs, thiseffectmay

beofclinicalrelevance.

Dueto the possibilityofrhythmdisturbances, combinationtherapywith diltiazemand beta-blockers

must onlybeuseunder close clinicalandECGmonitoring,particularlyatthebeginningoftreatment.

Carbamazepine

Twowell-documentedcaseshavebeenreportedwherethecombinationofdiltiazemwith

carbamazepineresultedinneurotoxicity.Concomitantuse mayresultinincreasedcirculating

carbamazepine levels.It isrecommended thattheplasma carbamazepine concentrationsbeassayed

and thatthedose should be adjusted ifnecessary.

Cyclosporin

Chronicadministrationofdiltiazemtopatientson cyclosporinhasresultedinincreasedtroughlevels

ofcyclosporin and consequent cyclosporininducednephrotoxicity. Although further studyisneeded,it

hasbeensuggested thatDiltiazemmayinterferewithmetabolismofcyclosporinvia hepatic

microsomalenzymeinhibition. ThepossibilitythatDiltiazemmayincrease serumcyclosporin

concentrationsshould be consideredifthe drugsareusedconcomitantly.Downward titrationof

cyclosporin dose mayberequired to minimise theriskofnephrotoxicpotential.

Dantroleneinfusion

Lethalventricular fibrillationisregularlyobservedinanimalswhenintravenousverapamiland

dantroleneareadministered concomitantly. Thecombinationofacalciumantagonist and dantrolene

istherefore potentiallydangerous.

Diazepam

Diazepamhasbeenreportedtocause asignificantdecrease indiltiazemplasmalevels. Theaverage

decreasein diltiazemconcentrationwasbetween20and30%. Three outofeightpatientsshowed

decreaseswhichwere greater than 50%.

Digoxin

Concomitant useofdiltiazemand digoxin mayresultinanadditiveeffect on conduction.Diltiazemis

knownto modifydigoxinpharmacokineticsin healthysubjects, inpatientswith cardiacinsufficiency

andinpatientswithchronicatrialfibrillation.Thefollowingeffectswere notedduringconventional

diltiazemco-administration:increasesin plasma digoxin concentrationsrangedfrom24to70%; the

renaldigoxin clearancedecreasedfrom86.9to62.8ml/minute;digoxin eliminationhalf-lifewas

prolonged from36.7to44.5hours.There isanincreasedriskofbradycardiawiththiscombination.

Cautionisrequiredwhendigoxiniscombinedwithdiltiazem, particularlyin theelderlyandwhenhigh

dosesare used.

H2 receptorantagonists

Concomitant usemayresult inincreaseplasma diltiazemconcentrations.Patientsreceivingdiltiazem

concurrentlywitha H2receptorantagonist shouldbecarefullymonitoredwhen initiatingor

discontinuingtherapywiththeH2receptor antagonist.An adjustment in the dailydose ofdiltiazem

maybenecessary.

Concurrentadministrationofdiltiazemwithcimetidineproduced anincrease in the plasma levelsof

single-dosediltiazemapproximately50% over controlanditsmetabolitedesacetyldiltiazem.

Insulin

Asinglecase hasbeen reported ofdecreasedinsulineffect after combinationtreatment ofinsulin and

diltiazemalthough the mechanismwasnotestablished.

Lithium

There isanincreasedriskoflithium-inducedneurotoxicity.

Organic nitrates-shortandlongacting

Increasedhypotensive effectsand faintnessmaybeseenduetoadditivevasodilatatingeffects. In

patientstreatedwithcalciumantagonists, theadditionofnitratederivativesshouldonlybecarried out

gradually,increasingdoses.Concurrent useofdiltiazemand sustained-releaseglyceryltrinitrate

preparationsistobeavoided.

Rifampicin

There isariskofdecreaseddiltiazemplasma levelsafter initiatingtherapywith rifampicin.Thepatient

should becarefullymonitoredwheninitiatingor discontinuing rifampicin treatment.

Rimonabant

Co-administrationwithdiltiazemresultsinanincreasein serumrimonabantlevels.

Theophylline

Concomitant useresultsinanincreasein circulatingtheophyllinelevels.Careshouldbeexercised

initiallyifit isnecessarytoco-administerdiltiazemand theophyllinedueto possible toxicity.

Simvastatin

Patientsondiltiazemtreated concomitantlywithsimvastatin80mg have aslightlyincreased riskof

myopathy.Thisisthought to be mediatedthroughdiltiazeminhibitionofCytochrome P450 3A4

enzymesand the P-glycoprotein drug transporterleadingtoincreasedsimvastatinplasma levels. The

riskofmyopathyisapproximately1%in thesepatients. Treatment withsimvastatin inapatienttaking

diltiazemshould bestartedatthe lowest possible doseandtitratedupwards. Ifdiltiazemtreatment is

tobeaddedtopatientsalreadytakingsimvastatin,considerareductionin statin dose and retitrate

against serumcholesterolconcentrations.

Foodand alcohol

Ingestionofgrapefruithasbeenshowntoincreasethehalf-life ofdiltiazemasaresult ofinhibitionof

gutwallmetabolismofdiltiazemduringabsorption.Theclinicalsignificance ofthisisunknown. Itis

recommended thatingestion ofgrapefruitor grapefruitjuice beavoided,or atleastdonottake

grapefruit/grapefruit juicewithin 10 hoursbefore or twohoursafter takingdiltiazem30mg and60 mg

tablets.

Overdosage

Thetoxicdoseinmanisnot known.Duetoextensivemetabolism, bloodlevelsafter a standarddose

ofdiltiazemcanvaryover tenfold,limiting the usefulnessofbloodlevelsinoverdose cases.There

have been29casesofdiltiazemoverdose in dosesrangingfromlessthan1 gto10.8g.16 ofthese

reportsinvolvedmultiple drugingestions.22reportsindicated patientshadrecoveredfromdiltiazem

overdose rangingfromlessthan1gto10.8g.Therewere sevenreportswithafataloutcome

although the amountofdiltiazemingestedwasunknown, multipledrugingestionswereconfirmedin

sixofthe sevenreports.

Signsandsymptoms

Theclinicaleffectsofacuteoverdose can involvepronouncedhypotensionpossiblyleadingto

collapse,sinusbradycardiawithorwithoutisorhythmicdissociation,heart block, cardiacfailure,and

atrio-ventricular conductiondisturbances.

Management

Most reportsofoverdose described some supportivemedicalmeasure and/ordrug treatment.

Bradycardia frequentlyresponded favourablytoatropine asdid heartblock, althoughcardiacpacing

wasalso frequentlyutilisedtotreatheart block. Fluidsandvasopressorswere used to maintainblood

pressure, and in casesofcardiacfailureinotropicagentswere administered.Inaddition,some

patientsreceivedtreatment withventilatorysupport, gastriclavage,activatedcharcoal,and/or

intravenouscalcium. Evidence oftheeffectivenessofintravenouscalciumadministrationtoreverse

thepharmacologicaleffectsofdiltiazemoverdosewasconflicting.

In the event ofoverdosageor exaggerated response,appropriatesupportive measuresshould be

employedinadditiontogastriclavage.Diltiazemdoesnot appear toberemovedbyperitoneal

dialysesor haemodialysis.Basedontheknownpharmacologicaleffectsofdiltiazemand/orreported

clinicalexperiences,the following measuresmaybeconsidered:

Bradycardia

Administer atropine(0.60to 1.0mg). Ifthere isnoresponse tovagalblockade administer isoprenaline

cautiously.

High-degreeatrioventricularblock

Treat asfor bradycardia above. Fixedhigh-degreeatrioventricularblockshouldbe treatedwith

cardiacpacing.

Cardiac failure

Administer inotropicagents(e.g.isoprenaline, dopamine, ordobutamine)and diuretics.

Hypotension

Administer vasopressors(e.g.dopamineornoradrenalineacid tartrate).

Actualtreatment anddosage shoulddependontheseverityofthe clinicalsituation and the judgement

andexperience ofthe treatingphysician.

Pharmaceuticalprecautions

Instructionsfor use/handling

Nil.

Incompatibilities

Noneknown.

Specialprecautionsfor storage

Storeatorbelow25°C.Protect fromlightandmoisture.

Medicineclassification

PrescriptionMedicine

Packagequantities

Packsof90tabletsin cartonedblister strips.

Furtherinformation

List ofexcipients

Microcrystallinecellulose,lactose,hydrogenated castor oil, povidone,polyethyleneglycol, sodium

starch glycollate,silicondioxide, magnesiumstearate,hydroxypropylmethylcellulose,stearicacid,

titaniumdioxide.

Nameandaddress

NovartisNew ZealandLimited

PrivateBag 65904 MairangiBay

AUCKLAND0754

Telephone: (09) 361 8100

Dateofpreparation

21January2010

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