Dilzem

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Diltiazem hydrochloride 60 mg;  ;  ;  ;  
Available from:
Douglas Pharmaceuticals Limited
INN (International Name):
Diltiazem hydrochloride 60 mg
Dosage:
60 mg
Pharmaceutical form:
Film coated tablet
Composition:
Active: Diltiazem hydrochloride 60 mg         Excipient: Aluminium hydroxide gel Hydrogenated castor oil Lactose monohydrate Magnesium stearate Methacrylic acid copolymer Opadry white Y-1R-7000B Purified talc
Units in package:
Blister pack, 1x30, 30 tablets
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Teva API India Ltd
Product summary:
Package - Contents - Shelf Life: Blister pack, - 30 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, plastic, - 100 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, plastic, - 500 tablets - 36 months from date of manufacture stored at or below 25°C - Bottle, plastic, - 1000 tablets - 36 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-4079a
Authorization date:
1986-11-27

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Information

DILZEM™

diltiazemhydrochloride30mgand60mgtablets

Whatisinthisleaflet

ThisleafletanswerssomecommonquestionsaboutDILZEMtablets.Itdoesnotcontainallthe

availableinformation.

Itdoesnottaketheplaceoftalkingtoyourdoctorandpharmacist.

Allmedicineshaverisksandbenefits.YourdoctorweighedtherisksofyoutakingDILZEMtablets

againstthebenefitsthismedicineisexpectedtohaveforyou.

Ifyouhaveanyconcernsabouttakingthismedicine,askyourdoctororpharmacist.

Keepthisleafletwiththemedicine

Youmayneedtoreaditagain.

WhatDILZEMtabletsareusedfor

DILZEMbelongstoagroupofmedicinesknownascalciumchannelblockersorcalciumantagonists.

DILZEMtabletsareusedtopreventanginapectoris,asyndromethatarisesfrominadequateoxygen

supplytotheheartmuscle.OxygensupplydependsonbloodflowandDILZEMactsbyopeningup

bloodvessels,lettingmorebloodreachtheheart.Itdoesnotchangetheamountofcalciuminyour

bloodorbones.

Anginaisseverepaininthechestthatmaybeduetothebloodvesselsofthehearttighteningoran

obstructionrestrictingbloodflow.Exercise,whichdemandsanincreasedoxygensupply,canbring

aboutangina.

YourdoctormayhaveprescribedDILZEMtabletsforanotherreason.

AskyourdoctorifyouhaveanyquestionsaboutwhyDILZEMtabletshavebeenprescribedforyou.

Thismedicineisavailableonlywithadoctor'sprescription.

BeforeyoutakeDILZEMtablets

Whenyoumustnottakeit

DonottakeDILZEMtabletsifyouhavehadanallergyto:

Diltiazem

Othercalciumchannelblockers

Anyoftheingredientslistedattheendofthisleaflet

SymptomsofanallergicreactiontoDILZEMtabletsmayinclude:

Shortnessofbreath,wheezingordifficultybreathing

Swellingoftheface,lips,tongueorotherpartsofthebody

Rash,itchingorhivesoftheskin

DonottakeDILZEMtabletsifyouhaveanyofthefollowingmedicalconditions:

Sick-sinussyndromeunlessyouhaveapacemaker

Thisisacomplextypeofcardiacarrhythmiacausinganabnormalrhythm(contraction/relaxation)

oftheheart.

SecondorthirddegreeAVblock

Theheartcontractsandrelaxesasasmallelectricalimpulsetravelsthroughit.Any

disturbance/blockofthepathtakenbytheimpulsewilleffecttheheartbeat.FirstdegreeAV

blockresultsindelayedimpulse.SeconddegreeAVblockresultsinoccasionalblockwhilethird

degreeistotalblock.

Hypotension-lowbloodpressure

Heartfailureorbradycardia

Bradycardiaisslowheartbeat

Anabnormalreactiontodiltiazem

DonottakeDILZEMtabletsifyouarepregnant

DonottakeDILZEMtabletsifthepackagingistornorshowssignsoftamperingorifthetablets

showvisiblesignsofdeterioration.

DonottakeDILZEMtabletsaftertheexpirydate(EXP)printedonthepack.

Ifyoutakethismedicineaftertheexpirydatehaspassed,itmaynotworkaswell.

Beforeyoustarttakingit

Tellyourdoctororpharmacistifyouareallergictoanyothermedicines,foods,dyesor

preservatives.

Tellyourdoctorifyouhaveorhaveeverhadanyotherhealthproblems/medicalconditions,

including:

FirstdegreeAVblock-slowheartrate

Heartfailure

Liverorkidneydisease

Diabetes-disorderofsugarmetabolism/control

Tellyourdoctorifyouarepregnantorintendtobecomepregnant.

ThereislimitedinformationonthesafetyofDILZEMtabletsinpregnancy.Yourdoctorwilldiscussthe

risksandbenefitsoftakingthismedicineduringpregnancy.

Tellyourdoctorifyouarebreastfeedingorplantobreastfeed.

ThesafetyofDILZEMininfantsandchildrenisnotwellknownandanalternativemethodofinfant

feedingshouldbeused.

Ifyouare65yearsorolder,youshouldbeespeciallycarefulwhiletakingDILZEM.Reportanyside

effectspromptlytoyourdoctor.Aspeoplegrowolder,theyaremorelikelytogetsideeffectsfrom

medicines.

DonotstoptakingDILZEMunlessadvisedtobyyourdoctor.

Suddenwithdrawalmaycausesevereangina

DILZEMtabletsareunlikelytoproduceaneffectontheabilitytodriveorusemachinery,

however,careshouldbetakenuntilyouknowhowthismedicineaffectsyou.

Thereisnoevidencethismedicineisaddictive

Takingothermedicines

Tellyourdoctorifyouaretakinganyothermedicines,includingmedicinesthatyoubuywithouta

prescriptionfromyourpharmacy,supermarketorhealthfoodshop.Somemedicinesmayinterferewith

DILZEMtablets.Theseinclude:

beta-blockers-medicinesusedtotreatdisordersoftheheartandbloodvesselssuchashighblood

pressure,anginaandcardiacarrhythmia

digoxin-amedicineusedtotreatacertaintypeofcardiacarrhythmia

cimetidine-amedicineusedtotreatrefluxandstomachulcers

diazepam-amedicineusedtotreatanxiety

cyclosporin-amedicineusedtosuppresstheimmunesystem

amiodarone-amedicineusedtotreatacertaintypeofcardiacarrhythmia

carbamazepine-amedicineusedtotreatseizures

enflurane-aninhaledanaesthetic

nitroglycerin-amedicineusedtotreatangina,heartfailureandheartattacks

theophylline-amedicineusedtotreatasthma

grapefruit-grapefruitshouldbeavoidedornotconsumedlessthan10hoursbeforeor2hours

aftertakingDILZEM30mgand60mgtablets.Grapefruitinterfereswiththe

metabolism/processingofDILZEMtablets

Yourdoctorandpharmacistmayhavemoreinformationonmedicinestobecarefulwithoravoidwhile

takingthismedicine

HowDILZEMtabletsaretaken

HowDILZEMtabletsaretaken

DILZEMtabletsshouldbetakenwithafullglassofwaterasinstructedbyyourdoctororpharmacist.

Theyshouldbetakenwholeandnotchewed.

Tabletsareusuallytakenfourtimesdailybeforemealsandatbedtime.

Yourdoctorwilldecidewhatdoseof,andforhowlongyoushouldtakeDILZEMtablets.This

dependsonyourmedicalconditionandotherfactors,suchasyourweight.

Carefullyfollowalldirectionsgiventoyoubyyourdoctor.Theirdirectionsmaydifferfromthe

informationcontainedinthisleaflet.Ifyoudonotunderstandtheinstructionsonthelabel,askyour

doctororpharmacistforhelp.

Ifyouforgettotakeit

Ifitisalmosttimeforyournextdose,skipthedoseyoumissedandtakeyournextdosewhenyouare

meantto.Otherwise,takeitassoonasyourememberandthengobacktotakingitasyouwould

normally.

Donottakeadoubledosetomakeupforthedosethatyoumissed.

Ifyouarenotsurewhattodo,askyourdoctororpharmacist.

Ifyouhavetroublerememberingwhentotakeyourmedicine,askyourpharmacistforsomehints.

WhileyouareusingDILZEMtablets

Thingsyoumustdo

Besuretokeepallofyourdoctor'sappointmentssothatyourprogresscanbechecked.

IfyoubecomepregnantwhileyouaretakingDILZEMtablets,tellyourdoctor.

Tellallthedoctors,dentistsandpharmacistswhoaretreatingyouthatyouaretakingDILZEMtablets.

Ifyouplantohavesurgerythatneedsageneralanaesthetic,tellyourdoctorordentistthatyouare

takingDILZEMtablets

Thingsyoumustnotdo

DonotstoptakingDILZEMtabletsorlowerthedosagewithoutcheckingwithyourdoctor.Stopping

thetabletssuddenlymaybringonananginaattack.

YourdoctormaywantyoutograduallyreducetheamountofDILZEMtabletsyouareusingbefore

stoppingcompletely.

Donotletyourselfrunoutoftabletsovertheweekendorholidays.

DonotgiveDILZEMtabletstoanyoneelse,eveniftheyhavethesameconditionasyou.

SideEffects

TellyourdoctororpharmacistassoonaspossibleifyoudonotfeelwellwhileyouaretakingDILZEM

tablets.

Allmedicinescanhavesideeffects.Sometimestheyareserious,mostofthetimetheyarenot.Youmay

needmedicaltreatmentifyougetsomeofthesideeffects.

Tellyourdoctorimmediatelyifyounoticeanyofthefollowing:

swellingofextremitiessuchasanklesorfingers

headacheanddizziness

stomachdiscomfitwithnauseaandvomiting

rashandtiredness

skinreactions

unusualheartrhythm

chestpain

shortnessofbreath

blurredvision

painfulmuscles

Othersideeffectsnotlistedabovemayoccurinsomepatients.

Tellyourdoctororpharmacistifyounoticeanythingelsethatismakingyouunwell

Overdose

Immediatelytelephoneadoctor,orthePoisonsInformationCentre(telephone0800POISONand0800

764766)orgototheaccidentandEmergencyDepartmentatyournearesthospital,ifyouthinkyouor

anyoneelsemayhavetakentoomanyDILZEMtablets.Dothiseveniftherearenosignsofdiscomfort

orpoisoning.

Storage

StoreDILZEMtabletsbelow30°C.

DonotstoreDILZEMtabletsinthebathroomornearasink.Donotleaveitinthecaronhotdays.

Heatanddampnesscandestroysomemedicines.

Keepyourtabletsintheoriginalpacktheyareprovidedinuntilitistimetotakethem.Ifyoutakethe

tabletsoutofthepacktheymaynotkeepwell.

Keepitoutofreachofchildren.Alockedcupboardatleastone-and-a-halfmetresabovethegroundisa

goodplacetostoremedicines.

Disposal

Ifyourdoctortellsyoutostoptakingthismedicineorthetabletshavepassedtheirexpirydate,askyour

pharmacistwhattodowithanythatareleftover

pharmacistwhattodowithanythatareleftover

Productdescription

Whatitlookslike

DILZEM30mgTablet:DiltiazemHCl30mgisawhite,circular,film-coated,biconvextabletof

approximately6mmdiameterembossed"D"ononeside.

DILZEM60mgTablet:DiltiazemHCl60mgisawhitecapsuleshaped,film-coatedtablet,10mmin

lengthand5mmwide;withabreaklineand'DL60'engravedononeface.

DILZEM30mg&60mgtabletscomeinbottlesof100tabletsorblisterpacksof30tablets.

OtherIngredients

DILZEM30mgand60mgtablets:Lactose,CutinaHR,Aluminiumhydroxidegeldried,Eudragit

NE30D,Talc,andMagnesiumstearateinthecoreandOpadrywhite(Y-IR-7000B)inthecoating.

Sponsor

DouglasPharmaceuticalsLtd

CentralParkDrive,Lincoln

AUCKLAND1008

DateofPreparation:7 th

January2004

1 | P a g e

New Zealand Data Sheet

1.

PRODUCT NAME

Dilzem® 30 mg film coated tablets

Dilzem® 60 mg film coated tablets

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Diltiazem hydrochloride 30 mg

Diltiazem hydrochloride 60 mg

Excipient(s) with known effect:

Dilzem tablets contain lactose. For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Dilzem 30 mg tablet: a white, circular, film-coated, biconvex tablet of approximately 6mm

diameter embossed "D" one side.

Dilzem 60 mg tablet: a white capsule shaped, film-coated tablet, 10mm in length and 5mm wide;

with a breakline and ‘DL60’ engraved on one face.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications

Angina pectoris due to coronary artery spasm and chronic stable angina.

4.2.

Dose and method of administration

Dose

Adults

Initially 30 mg three to four times daily increasing to 240 mg daily in divided doses. The

maximum recommended dose is 360 mg daily.

Special populations

Elderly population

Pharmacokinetics of diltiazem in elderly patients has not been fully elucidated. Preliminary

results in elderly patients (over 65 years old) suggest that a lower dosage might be required in

this age group.

2 | P a g e

Hepatic and renal impairment

There are few available data concerning dosage requirements in patients with impaired renal or

hepatic function. Dilzem should be used with caution in patients with hepatic or renal

impairment. If diltiazem must be used in these patients, the dosage should be carefully and

gradually adjusted depending on patient tolerability and responses.

Concomitant use with other cardiovascular agents

Sublingual glyceryl trinitrate may be taken as required to abort acute anginal attacks during

Dilzem therapy.

Dilzem may be safely co-administered with short- and long-acting nitrates.

Paediatric population

Safety and efficacy in children aged has not been established. Therefore, diltiazem is not

recommended for use in children.

Method of Administration

Oral administration.

4.3.

Contraindications

Patients with sick-sinus syndrome except in the presence of a functioning ventricular

pace-maker.

Patients with second or third degree AV block.

Patients with hypotension (< 90mmHg systolic).

Severe congestive heart failure or bradycardia.

Idiosyncrasy to diltiazem.

Pregnancy.

4.4.

Special warnings and precautions for use

Cardiac Conduction: Caution is required in cases of first degree AV block. Diltiazem prolongs AV

node refractory periods but not sinus node recovery times (except in sick sinus syndrome). This

may result in slowing of heart rate, prolongation of the PR interval or even second or third

degree AV block. Concomitant use of diltiazem with beta-blockers or digitalis may result in

additive effects on cardiac conduction.

Congestive Heart Failure: Caution must be exercised in patients with congestive heart failure.

Hypotension: Arteriolar dilation produced by diltiazem administration may occasionally give rise

to symptomatic hypotension.

Acute Hepatic Injury: In rare instances, patients receiving diltiazem have exhibited reversible

acute hepatic injury as evidenced by moderate to extreme elevations of liver enzymes.

3 | P a g e

Respiratory Events: The use of diltiazem may induce bronchospasm, including asthma

aggravation, especially in patients with pre-existing bronchial hyper-reactivity. Cases have also

been reported after dose increase. Patients should be monitored for signs and symptoms of

respiratory impairment during diltiazem therapy.

Concomitant Administration with Beta-Blockers: Diltiazem may cause marked prolongation of

atrioventricular conduction in a small number of patients, and caution is advised if combination

therapy is considered due to the risk of bradycardia. Such a combination should not be used in

patients with depressed left ventricular function and conduction system disease.

Abrupt Withdrawal: The sudden withdrawal of diltiazem has been associated with severe

angina.

Use in Diabetics: Diltiazem influences insulin secretion and peripheral action as a result of

inhibition of calcium influx into cells so caution is required if diltiazem is considered for use in

diabetic patients.

Use with Amiodarone: Caution is required if consideration is being given to the use of diltiazem

and amiodarone in combination especially in the presence of underlying dysfunction of the sinus

node such as bradycardia, sick sinus syndrome or partial AV block.

Concomitant Use with Digoxin: The combination of diltiazem with digitalis may give rise to

additive effects in prolonging AV conduction.

General: Diltiazem is extensively metabolised by the liver, metabolites being eliminated by the

kidneys and in bile. It should be used with caution & in reduced dosage in patients with impaired

renal or hepatic function. Liver function tests should be monitored during prolonged use as very

rare transaminase elevations have been noted.

4.5.

Interaction with other medicines and other forms of interaction

The combination of diltiazem with beta-blockers may produce a positive clinical response in

patients with angina pectoris. Care is required, however, since AV conduction may be prolonged

leading to serious deleterious effects (See Warnings and Precautions). Diltiazem is known to

modify digoxin pharmacokinetics in healthy subjects, and in patients with cardiac insufficiency or

chronic atrial fibrillation.

These modifications involved: an increase in plasma digoxin concentration of 24-70%, a decrease

in mean renal digoxin clearance from 86.9 mL/min to 62.8 mL/min, and an increase in the mean

digoxin elimination half-life from 36.7 h to 44.5 h.

Concurrent administration of diltiazem with cimetidine results in an increase in both diltiazem

and desacetyl diltiazem plasma levels. Concomitant administration of diltiazem with diazepam

causes a significant decrease, averaging between 20-30%, in diltiazem plasma levels. The

4 | P a g e

combination of diltiazem with amiodarone may have additive adverse effects on sinus node

function and myocardial contractility.

Chronic administration of diltiazem to patients on cyclosporin-A will result in increased trough

levels of cyclosporin-A.

Diltiazem HCl should not be administered with carbamazepine as two well-documented cases

have been reported where combination resulted in neurotoxicity.

A single case has been reported of cardiac arrhythmia involving sinus arrest and impaired AV

conduction after administration of enflurane and diltiazem together.

A single case has been reported of decreased insulin effect after combination treatment of

insulin and diltiazem although the mechanism was not established.

Concurrent use of diltiazem and sustained-release nitroglycerin preparations is to be avoided.

Care should be exercised initially if it is necessary to coadminister diltiazem and theophylline due

to possible toxicity.

Ingestion of grapefruit has been shown to increase the half-life of diltiazem as a result of

inhibition of gut wall metabolism of diltiazem during absorption. The clinical significance of this

is unknown. It is recommended that ingestion of grapefruit or grapefruit juice be avoided, or at

least do not take grapefruit/grapefruit juice within 10 hours before or two hours after taking

diltiazem 30 mg and 60 mg tablets.

Patients on diltiazem treated concomitantly with simvastatin 80 mg have a slightly increased risk

of myopathy. This is thought to be mediated through diltiazem inhibition of Cytochrome P 450

3A4 enzymes and the P-glycoprotein drug transporter leading to increased simvastatin plasma

levels. The risk of myopathy is approximately 1% in these patients. Treatment with simvastatin in

a patient taking diltiazem hydrochloride should be started at the lowest possible dose and

titrated upwards. If diltiazem hydrochloride treatment is to be added to patients already taking

simvastatin, consider a reduction in statin dose and retitrate against serum cholesterol

concentrations.

4.6.

Fertility, pregnancy and lactation

Pregnancy

There are no well-controlled studies of the use of diltiazem HCl in pregnant women. There is the

potential to produce foetal hypoxia associated with maternal hypotension therefore, diltiazem

HCl should only be used if the potential benefit justifies the potential risk to the foetus.

Breast-feeding

5 | P a g e

Diltiazem HCl is excreted in human milk and breast milk concentrations may approximate serum

levels. Since the safety and effectiveness of diltiazem HCl in infants and children has not been

established an alternative method of infant feeding should be instituted if use of diltiazem HCl is

deemed essential.

Fertility

No data available.

4.7.

Effects on ability to drive and use machines

Patients should be warned about the potential for dizziness and fatigue, and advised not to drive

or operate machinery if these symptoms occur or until their individual susceptibility is known.

4.8.

Undesirable effects

Side effects are rare. The most common occurrences are: gastrointestinal discomfort with

nausea and vomiting, swelling and oedema, arrhythmia, headache and dizziness, rash and

fatigue. Mild to moderate elevation of alkaline phosphatase and transaminases occurs rarely.

The committee on safety of medicines in the U.K. has noted the following adverse effects:

serious skin reactions (exfoliative dermatitis and epidermal necrolysis), hypotension and one

case of agranulocytosis. Bradycardia and heartblock (sinoatrial &/or atrioventricular) have also

been noted as have muscular (including myalgia) effects and ocular (including abnormal vision)

changes.

Atrioventricular block is an uncommon but potentially serious adverse effect of diltiazem

treatment and the risk is increased by concurrent use of a beta-blocker.

Bronchospasm (including asthma aggravation) has also been reported.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It allows

continued monitoring of the benefit/risk balance of the medicine. Healthcare professionals are

asked to report any suspected reactions https://nzphvc.otago.ac.nz/reporting/

4.9.

Overdose

The oral LD

in mice and rats ranged from 415 to 740 mg/kg and from 560 to 810 mg/kg,

respectively. The intravenous LD

in these species was 60 and 38 mg/kg, respectively. The oral

in dogs is considered to be in excess of 50 mg/kg, while lethality was seen in monkeys at

360 mg/kg. The toxic dose in man is not known. Due to extensive metabolism, blood levels after

a standard dose of diltiazem can vary over tenfold, limiting the usefulness of blood levels in

overdose cases. There have been 29 cases of diltiazem overdose in doses ranging from less than

1 g to 10.8 g. Sixteen of these reports involved multiple drug ingestions. Twenty-two reports

indicated patients had recovered from diltiazem overdose ranging from less than 1 g to 10.8 g.

6 | P a g e

There were seven reports with a fatal outcome; although the amount of diltiazem ingested was

unknown, multiple drug ingestions were confirmed in six of the seven reports.

Symptoms

The clinical effects of acute overdose can involve pronounced hypotension possibly leading to

collapse, sinus bradycardia with or without isorthythmic dissociation, heart block, cardiac

failure,and atrio-ventricular conduction disturbances. Most reports of overdose described some

supportive medical measure and/or drug treatment.

Bradycardia frequently responded favourably to atropine as did heart block, although cardiac

pacing was also frequently utilised to treat heart block. Fluids and vasopressors were used to

maintain blood pressure, and in cases of cardiac failure inotropic agents were administered. In

addition, some patients received treatment with ventilatory support, gastric lavage, activated

charcoal, and/or intravenous calcium. Evidence of the effectiveness of intravenous calcium

administration to reverse the pharmacological effects of diltiazem overdose was conflicting.

Treatment

In the event of overdose or exaggerated response, appropriate supportive measures should be

employed in addition to gastrointestinal decontamination. Diltiazem does not appear to be

removed by peritoneal or haemodialysis.

For advice on the management of overdose please contact the National Poisons Centre on 0800

POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties

Pharmacotherapeutic group: Calcium channel blocker, Benzothiazepine derivatives; ATC code:

C08D B01

Mechanism of action

Diltiazem, a benzothiazepine, is a calcium antagonist, inhibiting calcium ion entry into smooth

muscle cells by blockade of slow calcium channels. It is believed to act as follows:

Angina due to coronary artery spasm: Diltiazem is a potent dilator of both epicardial and

subendocardial coronary arteries and it inhibits spontaneous coronary artery spasm.

Exertional angina: Diltiazem is able to produce increases in exercise tolerance via reduction in

heart rate, systemic blood pressure and dilation of coronary arteries. In animal models diltiazem

interferes with the slow inward (depolarising) current in excitable tissue producing: relaxation of

coronary vascular smooth muscle, dilation of both large and small coronary arteries without

inducing a negative inotropic effect, and increased coronary blood flow accompanied by dose

dependent decreases in systemic blood pressure and peripheral resistance.

7 | P a g e

Evaluation of glucose and lipid homeostasis in diabetic and non-diabetic subjects treated with

calcium antagonists indicates that diltiazem does not affect energy metabolism in the majority

of individuals.

5.2.

Pharmacokinetic properties

Diltiazem is almost completely absorbed after oral administration but first pass metabolism

limits its systemic availability to about 50%. Although detectable in plasma between 30-60

minutes after administration, peak levels are normally achieved 2-4 hours after administration of

the 30 mg or 60 mg tablets.

Diltiazem is distributed to the liver, kidney, lung, spleen, heart and brain with tissue

concentration decreasing in that order. Plasma protein binding accounts for 77-86% of plasma

diltiazem, 35-40% being bound to albumin and the rest to a-glycoprotein.

Diltiazem is extensively metabolised in the liver by deacetylation, N-demethylation and O-

demethylation such that only 0.1-4% of unchanged diltiazem appears in the urine. Five

metabolites have been identified. Desacetyldiltiazem is normally present in plasma at levels of

10-20% of the parent medicine and is 25-50% as potent a vasodilator as diltiazem. Some studies

have, however, shown that this metabolite can accumulate during multiple oral dosing and the

plasma concentration may exceed that of the parent medicine. Another metabolite, N-mono-

demethyl-diltiazem may be about 20% as potent as the parent medicine. The other metabolites

are devoid of pharmacological activity.

Studies in rats have shown that after administration of

C-diltiazem, greater than 90% of the

can be removed from urine and faeces in 72 hours. Excretion of diltiazem metabolites in the

faeces seems to be the main route of elimination since more than 60% of the dose is excreted

into the bile in 24 hours and 65% into the faeces in 72 hours. There is extensive enterohepatic

circulation.

The plasma half-life of diltiazem is approximately 3.5 hours. Therapeutic blood levels appear to

be in the range of 50-200 ng/mL.

Plasma levels above 50 ng/mL are achieved between 1-1.5 hours and are maintained for

approximately 8 hours after administration of the 30 mg and 60 mg tablets.

Little information is available as to the effect of age, renal or hepatic dysfunction on the

pharmacokinetic profile, other than that the more pronounced anti-hypertensive effect seen in

the elderly may be due to a decreased clearance.

Diltiazem hydrochloride is excreted in breast milk.

5.3.

Preclinical safety data

Animal subacute toxicity and chronic toxicity studies in dogs and rats indicated hepatic damage

occurred at high dosages. Such damage was reversible when the drug was discontinued.

8 | P a g e

Reproduction studies in mice, rats and rabbits showed administration of high doses resulted in

embryo and foetal deaths. Skeletal abnormalities were also observed. Peri-natal and post-natal

studies showed reduction in pup weights and survival rates with an increased incidence of still

births.

The oral LD

in mice and rats ranges from 415-740 mg/kg and 560-810 mg/kg respectively. The

intravenous LD

in both species is 60 mg/kg and 38 mg/kg respectively. The oral LD

in dogs is

considered to be in excess of 50 mg/kg. Lethality in monkeys was seen at 360 mg/kg. The toxic

dose in man is unknown, but blood levels in excess of 800 ng/mL have not been associated with

toxicity.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients

Dilzem tablets contain the following excipients:

Lactose, Cutina HR, Aluminium hydroxide gel dried, Eudragit NE30D, Talc, and Magnesium

stearate for the core and Opadry white (Y-IR-7000B) for coating.

6.2.

Incompatibilities

Not applicable.

6.3.

Shelf life

36 months.

6.4.

Special precautions for storage

Store at or below 25°C.

6.5.

Nature and contents of container

Bottles of 100, 500 or 1,000 tablets.

Blister packs of 30 tablets.

Not all strengths or pack sizes may be marketed.

6.6.

Special precautions for disposal and other handling

No special requirements for disposal.

7.

MEDICINE SCHEDULE

Prescription Medicine

9 | P a g e

8.

SPONSOR

Douglas Pharmaceuticals Ltd

P O Box 45 027

Auckland 0651

New Zealand

Phone: (09) 835 0660

9.

DATE OF FIRST APPROVAL

Dilzem 30 mg: 10 April 1989

Dilzem 60 mg: 27 November 1986

10.

DATE OF REVISION OF THE TEXT

1 November 2018

Summary table of changes

Section Changed

Summary of new information

SPC format

4.4, 4.8

Additional information on bronchospasm

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