Cardizem CD

New Zealand - English - Medsafe (Medicines Safety Authority)

Buy It Now

Active ingredient:
Diltiazem hydrochloride 360 mg (30-35 mesh nonpareil seed)
Available from:
sanofi-aventis new zealand limited
INN (International Name):
Diltiazem hydrochloride 360 mg (30-35 mesh nonpareil seed)
Dosage:
360 mg
Pharmaceutical form:
Modified release capsule
Composition:
Active: Diltiazem hydrochloride 360 mg (30-35 mesh nonpareil seed) Excipient: Acetyl tributyl citrate Brilliant blue FCF   Diethyl phthalate Ethanol Gelatin Methacrylic acid copolymer Povidone Purified talc   Purified water   Simeticone Sodium laurilsulfate Sugar spheres Titanium dioxide  
Units in package:
Blister pack, PVD/PE/PVDC Alu sample pack, 7 capsules
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Finorga SA
Therapeutic indications:
CARDIZEM CD is indicated for the treatment of hypertension. It may be used alone or in combination with other antihypertensive medications such as diuretics.
Product summary:
Package - Contents - Shelf Life: Blister pack, PVD/PE/PVDC Alu sample pack - 7 capsules - 24 months from date of manufacture stored at or below 25°C protect from light and moisture - Blister pack, PVD/PE/PVDC Alu - 10 capsules - 24 months from date of manufacture stored at or below 25°C protect from light and moisture - Bottle, plastic, HDPE sample pack - 7 capsules - 36 months from date of manufacture stored at or below 25°C protect from light and moisture - Bottle, plastic, HDPE - 10 capsules -   - Bottle, plastic, HDPE - 28 capsules -   - Bottle, plastic, HDPE - 30 capsules - 24 months from date of manufacture stored at or below 25°C protect from light and moisture - Bottle, plastic, HDPE - 100 capsules -   - Calendar pack, PVD/PE/PVDC Alu - 28 capsules - 24 months from date of manufacture stored at or below 25°C protect from light and moisture - Calendar pack, PVD/PE/PVDC Alu - 30 capsules - 24 months from date of manufacture stored at or below 25°C protect from light and moisture - Calendar pack, PVD/PE/PVDC Alu - 100 capsules - 24 months from date of manufacture stored at or below 25°C protect from light and moisture
Authorization number:
TT50-3687/1d
Authorization date:
1999-06-23

Cardizem

®

CD capsules

and Cardizem

®

tablets

Diltiazem hydrochloride

Consumer Medicine Information (CMI)

What is in this leaflet

This leaflet answers some common

questions about Cardizem CD

capsules and Cardizem tablets. It

does not contain all the available

information.

It does not take the place of talking to

your doctor or pharmacist.

All medicines have risks and

benefits. Your doctor has weighed

the risks of you taking these

medicines against the benefits they

expect it will have for you.

Keep this leaflet with the medicine.

You may need to read it again.

What these medicines

are used for

You have been prescribed either

Cardizem CD capsules or Cardizem

tablets. These medicines both contain

an active ingredient called diltiazem

hydrochloride. The difference

between these is that Cardizem CD is

designed to release the active

ingredient slowly so that it works

over 24 hours and can be taken once

a day (CD stands for "controlled

delivery"). Cardizem tablets release

the active ingredient faster and so

must be taken more often (3-4 times

a day, as your doctor has instructed).

These medicines belong to a group of

medicines called calcium channel

blockers or calcium antagonists.

They work by opening up blood

vessels, which lowers blood pressure

and lets more blood and oxygen

reach the heart. They do not change

the amount of calcium in your blood

or bones.

Cardizem tablets are used to prevent

angina.

Cardizem CD capsules are used to

prevent angina or to treat

hypertension (high blood pressure).

Angina is a pain or uncomfortable

sensation in the chest, often

spreading to the arms or neck and

sometimes to the shoulders and back.

The pain of angina is due to a

shortage of oxygen to the heart.

High blood pressure can have many

different causes, including kidney

disease, hardening of the arteries and

some hormone imbalances. However,

the vast majority of people with high

blood pressure have no identifiable

cause for it. If left untreated, high

blood pressure can lead to serious

health problems such as a stroke or

heart attack.

Your doctor may have prescribed

these medicines for another reason.

Ask your doctor if you have any

questions about why these

medicines have been prescribed for

you.

There is no evidence that these

medicines are addictive.

These medicines are available only

with a doctor's prescription.

Before you take these

medicines

When you must not take

them:

Do not take these medicines:

If you have had any of the

following medical conditions:

certain types of abnormal heart

rhythm

hypotension (low blood pressure)

heart attack or other heart-related

complications

pulmonary congestion (fluid on

the lungs)

If you are currently taking any of the

following medications:

dantrolene (muscle relaxant)

ivabradine (an antiviral)

If you have an allergy to:

diltiazem hydrochloride or any of

the ingredients listed at the end of

this leaflet

Symptoms of an allergic reaction to

these medicines may include:

asthma, wheezing or shortness of

breath

swelling of the face, lips or

tongue, which may cause

difficulty in swallowing or

breathing

hives, itching or skin rash

fainting

If you are pregnant, or intend to

become pregnant.

These medicines may affect your

developing baby if they are taken

during pregnancy.

CARDIZEM

CD CAPSULES AND CARDIZEM

TABLETS

If you are breastfeeding or intend

to breastfeed.

The active ingredient of these

medicines passes into breast milk and

may affect your baby.

If the packaging is torn or shows

signs of tampering or if tablets or

capsules do not look quite right.

If the expiry date (EXP) printed on

the pack has passed.

If you take this medicine after the

expiry date has passed, it may not

work as well.

If you are not sure whether you

should start taking these

medicines, contact your doctor.

Do not give these medicines to a

child.

The safety and effectiveness of these

medicines have not been established

in children.

Before you start to take it

Tell your doctor:

If you have any allergies to:

any other medicines

any other substances, such as

foods, preservatives or dyes

If you are pregnant or intend to

become pregnant.

Cardizem CD capsules and Cardizem

tablets should not be used during

pregnancy.

If you are breastfeeding or plan to

breastfeed.

Your doctor will discuss this

situation with you. A decision will

have to be made whether to

discontinue breastfeeding or

discontinue therapy taking into

consideration the importance of the

medicine.

If you have or have had any

medical conditions, especially the

following:

abnormal heart beat rhythm

hypotension (low blood pressure)

heart attack or other heart-related

complications

impaired renal (kidney) or hepatic

(liver) function

diabetes

asthma

Taking other medicines

Tell your doctor if you are taking

any other medicines, including any

that you buy without a

prescription from your pharmacy,

supermarket or health food shop.

Some medicines may interfere with

Cardizem CD capsules or Cardizem

tablets. These include:

dantrolene (a muscle relaxant)

aspirin

medications used to help prevent

blood clots (antiplatelets)

cilostazol (a medicine used to

treat blockage of blood vessels to

the legs)

Some other medicines for your

heart or high blood pressure (eg.

beta blockers, digoxin,

amiodarone, nitrates)

ciclosporin, which you may have

been given after an operation or

because of rheumatoid arthritis

rifampicin (an antibiotic)

cimetidine or ranitidine (for

ulcers or reflux)

diazepam (for depression, alcohol

withdrawal or anxiety)

phenytoin (for epilepsy)

carbamazepine (for bipolar

disorder or epilepsy)

lithium (for bipolar disorder)

theophylline (for asthma and

other breathing problems) certain

drugs used to treat prostate

problems

ivabradine (an antiviral)

inhaled anaesthetic agents such as

halothane, isoflurane, enflurane

(for surgery)

drugs used to lower your blood

cholesterol (including

simvastatin, lovastatin)

benzodiazepines or medicines

used as sedatives or to treat

anxiety such as midazolam,

triazolam

corticosteroids such as

methylprednisolone, prednisone,

cortisone

antiarrhythmics or medicines

used to treat irregular heart beats

medicines used during scans to

see images of your body

Cardizem CD capsules or Cardizem

tablets may themselves be affected,

or they may affect how well these

medicines work. You may need to

take different amounts of your

medicine, or you may need to take

different medicines. Your doctor will

advise you.

Your doctor and pharmacist may

have more information on

medicines to be careful with or to

avoid while taking Cardizem CD

capsules or Cardizem tablets.

How to take these

medicines

How much to take

Cardizem CD capsules can be

taken once a day, preferably at the

same time every day. Cardizem

tablets can be taken three or four

times a day. Your doctor will tell

you how often and how much

Cardizem CD or Cardizem tablets

to take. Follow all directions given

to you by your doctor and

pharmacist carefully. Write them

down if necessary.

If you do not understand the

instructions on the packaging of

these medicines, ask your doctor or

pharmacist for help.

How to take it

Swallow the capsules or the tablets

with a glass of water. Do not chew

them.

When to take it

Take these medicines at the same

time(s) every day.

CARDIZEM

CD CAPSULES AND CARDIZEM

TABLETS

How long to take it

If you are not sure how long to

take your medicine, talk to your

doctor.

If you forget to take it

If you are taking these medicines

for angina, do not suddenly stop

taking them since this can cause

severe angina for a day or two.

If you forget to take a dose and it is

almost time for your next dose,

skip the dose you missed and take

your next dose when you are meant

to. Otherwise, take it as soon as

you remember, and then go back

to taking your tablets or capsules

as you would normally.

Do not take a double dose to make

up for the dose that you missed.

If you have trouble remembering to

take your medicine, ask your

pharmacist for some hints.

If you take too much

(overdose)

If you think that you or anyone

else may have taken too much of

these medicines, immediately

telephone your doctor or Poisons

Information Centre (Australia

telephone 13 11 26, New Zealand

telephone 0800 764766), or go to

the Accident and Emergency

Department at your nearest

hospital. Do this even if there is no

signs of discomfort or poisoning.

If you take too much of these

medicines, you may:

feel continuously light-headed or

dizzy

notice your heart beating very

slowly

feel pain, which could be severe,

in your left arm and chest.

If any of these occur, you should

get medical attention immediately.

While you are using

these medicines

Things you must do

Take these medicines exactly as

your doctor has prescribed.

If you do not follow your doctor's

instructions, you may not get relief

from your attacks of angina, or your

blood pressure may not be as well

controlled as it could be.

If you are taking these medicines

for angina, tell your doctor if you

continue to have angina attacks or

if they become more frequent.

Tell all your doctors, dentists and

pharmacists that you are taking

these medicines.

Tell your doctor or pharmacist

that you are taking Cardizem CD

capsules or Cardizem tablets if you

are about to be started on any new

medicine.

Things you must not do

Do not use these medicines to treat

any other complaints unless your

doctor says to.

Do not give these medicines to

anyone else, even if they have the

same condition as you.

As mentioned previously, if you are

taking these medicines for angina,

do not suddenly stop taking your

medicine since this can cause

severe angina for a day or two.

Things to be careful of

Be careful driving or operating

machinery until you know how

these medicines affect you.

These medicines may cause dizziness

and fainting in some patients,

especially when you first start to use

them. Make sure you know how you

react to these medicines before you

drive a car, operate machinery, or do

anything else that could be dangerous

if this happens to you.

Be careful not to overdo physical

activities when you first start using

these medicines.

You may feel better when you start

taking these medicines, but you will

need time to improve your physical

fitness.

Drinking grapefruit juice may

increase the effects of Cardizem

and Cardizem CD.

Get up slowly when getting out of

bed or standing up if you feel light-

headed, dizzy or faint.

If this is a problem and it gets worse

or continues, talk to your doctor.

Side effects

Tell your doctor or pharmacist as

soon as possible if you do not feel

well while you are using these

medicines.

These medicines help most people

with angina, and Cardizem CD will

help control most people's blood

pressure, but they may have

unwanted effects in a few people.

All medicines can have side effects.

Sometimes they are serious, but most

of the time they are not. You may

need medical treatment if you get

some of the side effects.

Ask your doctor or pharmacist any

questions you may have.

Tell your doctor if you notice any

of the following and they worry

you:

swelling or flushing (feeling hot

suddenly)

headache

nausea, vomiting, constipation,

diarrhoea, indigestion, gastric

pain

dizziness

confusion, hallucinations,

abnormal dreams, mental

depression or mood changes

trouble sleeping

nervousness, tremor

ringing or other persistent noise

in the ears

loss of memory

dry mouth

CARDIZEM

CD CAPSULES AND CARDIZEM

TABLETS

loss of appetite

weight increase

increased sensitivity to the sun

unusual movements or

uncontrollable movements

rash or an itchy, burning or

prickly sensation

small round, raised itchy areas on

the skin

weakness or tiredness

These side effects are usually mild.

Tell your doctor immediately if

you notice any of the following:

you feel continuously light

headed or dizzy

you notice your heart beating

irregularly, slowly or very

quickly

you feel pain, which may be

severe, in your left arm and chest

you have blisters and bleeding in

the lips, eyes, mouth, nose or

genitals

you have skin reactions such as

red, painful or itchy spots, blisters

or peeling of the skin.

you have difficulty breathing,

wheezing or coughing

These are serious side effects. You

may need urgent medical attention.

Serious side effects are rare.

Other side effects not listed above

may also occur in some patients.

Tell your doctor if you notice

anything else that is making you

feel unwell.

Ask your doctor or pharmacist if

you do not understand anything in

this section.

Do not be alarmed by this list of

possible side effects. You may not

experience any of them.

After taking these

medicines

Storage

Keep these medicines in their

container until it is time to take

them.

If you take the medicine out of its

container it may not keep well.

Keep these medicines in a cool, dry

place where it stays below 25°C.

Do not store them, or any other

medicine, in a bathroom or near a

sink. Do not leave them in the car

or on a windowsill.

Heat and dampness can destroy some

medicines.

Keep this medicine where young

children cannot reach it.

A locked cupboard at least one-and-a

half metres above the ground is a

good place to store medicines.

Disposal

If your doctor tells you to stop

taking your Cardizem medication,

or it has passed its expiry date, ask

your pharmacist what to do with

any tablets or capsules that are left

over.

Product description

What your medicine looks

like

Cardizem CD capsules

Cardizem CD capsules are available

in packs of 30 for the 180 mg and

240 mg strengths. Each blister strip is

calendarised and contains 15

capsules. For your first dose, take the

capsule labelled "Take this Capsule

First". Take the next doses according

to the day of the week which is

printed on the blister foil.

The 360 mg strength is available in a

bottle of 30 capsules.

All doses (180 mg, 240 mg and 360

mg) are two component capsules:

The 180 mg capsules are blue and

light turquoise

The 240 mg capsules are blue

The 360 mg capsules are white

and light blue

Cardizem tablets

Cardizem tablets are supplied in

plastic bottles of 90 tablets with a

seal in the mouth of the bottle. The

tablets are light yellow, speckled,

round and biconvex. The word

"Marion" is engraved on one side of

the tablet while the other side is

scored and engraved with "1772".

Ingredients

Cardizem CD 180 and 240 mg

capsules contain:

Diltiazem hydrochloride 180 mg or

240 mg, fumaric acid, purified talc,

non-pareil seeds (sucrose), colloidal

anhydrous silica, white beeswax,

ethylcellulose, castor oil, stearic acid,

methacrylic acid copolymers, tributyl

acetylcitrate, simethicone, gelatin,

brilliant blue FCF, black iron oxide

and titanium dioxide.

Cardizem CD 360 mg capsules

contain:

Diltiazem hydrochloride 360 mg,

non-pareil seed (sucrose), povidone,

sodium lauryl sulfate, diethyl

pthalate, purified talc, methacrylic

acid copolymers, tributyl

acetylcitrate, simethicone, titanium

dioxide, brilliant blue FCF, titanium

dioxide and gelatin.

Cardizem tablets contain:

Diltiazem hydrochloride 60 mg,

lactose monohydrate,

microcrystalline cellulose,

hypromellose, colloidal anhydrous

silica, magnesium stearate, methyl

hydroxybenzoate, sunset yellow FCF

CI 15985, quinoline yellow CI 47005

and a film-coating (Opadry

YS-5-7044 &

methylhydroxybenzoate).

Manufacturer/Distributor

Cardizem CD capsules and Cardizem

tablets are distributed by:

sanofi-aventis australia pty ltd

CARDIZEM

CD CAPSULES AND CARDIZEM

TABLETS

12-24 Talavera Road

Macquarie Park

NSW 2113

Australia

sanofi-aventis new zealand limited

Level 8, 56 Cawley Street

Ellerslie, Auckland, New Zealand

Australian Registration Numbers:

The following products are

available:

Cardizem CD capsules

180 mg: AUST R 46818

240 mg: AUST R 46822

360 mg: AUST R 75251*

Cardizem tablets

60 mg: AUST R 73179*

*denotes not available in New

Zealand

This leaflet was prepared in

September 2017

cardizem-cd-ccdsv11-cmiv15-sep17

CARDIZEM

CD CAPSULES AND CARDIZEM

TABLETS

New Zealand Data Sheet

Cardizem CD – Diltiazem Hydrochloride

cardizem-cd-ccdsv13-dsv17-20apr20

Page 1

NEW ZEALAND DATA SHEET

1

PRODUCT NAME

Cardizem CD 120 mg modified release capsules

Cardizem CD 180 mg modified release capsules

Cardizem CD 240 mg modified release capsules

Cardizem CD 360 mg modified release capsules

2

QUALITATIVE AND QUANTITATIVE COMPOSITION

Diltiazem hydrochloride 120 mg, 180 mg, 240 mg or 360 mg in sustained release form.

Chemically diltiazem hydrochloride is the hydrochloride salt of (2S, 3S)-5-(2-

Dimethylaminoethyl)-2, 3, 4, 5-tetrahydro-2-(4-methoxyphenyl)-4-oxo-1, 5-benzothiazepin-3-yl

acetate.

For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Modified release capsule

Cardizem CD is registered in 4 strengths:

120 mg:

Light turquoise/opaque capsule printed with “Cardizem CD 120 mg.”*

180 mg:

Light turquoise blue/blue capsule

240 mg:

Blue/blue capsule

360 mg:

Light blue/white capsule printed with “Cardizem CD 360 mg” in light blue ink*

Cardizem CD contains a white to off-white crystalline powder with a bitter taste. It is freely

soluble in water, methanol, and chloroform. Cardizem CD capsules contain a blend of beads with

controlled dissolution characteristics for once-a-day administration.

New Zealand Data Sheet

Cardizem CD – Diltiazem Hydrochloride

cardizem-cd-ccdsv13-dsv17-20apr20

Page 2

*Denotes presentations not available in New Zealand

4

CLINICAL PARTICULARS

4.1

THERAPEUTIC INDICATIONS

Cardizem CD is indicated for the treatment of hypertension. It may be used alone or in

combination with other antihypertensive medications such as diuretics.

Cardizem CD is also indicated for the management of chronic stable angina and angina due to

coronary artery spasm.

4.2

DOSE AND METHOD OF ADMINISTRATION

Patients controlled on diltiazem alone or in combination with other medications may be safely

switched to Cardizem CD at the nearest equivalent total daily dose. Subsequent titration to higher

or lower doses may be necessary and should be initiated as clinically warranted. There is limited

clinical experience with doses above 360 mg. Therefore, treatment with doses exceeding 360

mg/day is not recommended.

Adults

Hypertension

Dosage needs to be adjusted by titration to individual patient needs. When used as monotherapy,

reasonable starting doses are 180 to 240 mg once daily, although some patients may respond to

lower doses. Maximum antihypertensive effect is usually observed by 14 days of chronic therapy;

therefore, dosage adjustments should be scheduled accordingly. The usual dosage range studied

in clinical trials was 240 to 360 mg daily.

Angina

Dosages for the treatment of angina should be adjusted to each patient's needs, starting with a

dose of 120 mg or 180 mg once daily. Individual patients may respond to higher doses of up to

360 mg once daily. When necessary, titration may be carried out over a 7 to 14 day period.

Use in the Elderly

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 (see Section 4.4).

New Zealand Data Sheet

Cardizem CD – Diltiazem Hydrochloride

cardizem-cd-ccdsv13-dsv17-20apr20

Page 3

Impaired Hepatic or Renal Function

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

hepatic function. Diltiazem 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 (see Section 4.4).

CONCOMITANT USE WITH OTHER CARDIOVASCULAR AGENTS

Sublingual glyceryl trinitrate

may be taken as required to abort acute anginal attacks during

diltiazem therapy. Diltiazem may be safely co-administered with short- and long-acting nitrates.

Beta-blockers

(see Section 4.4).

Antihypertensives

- diltiazem has an additive antihypertensive effect when used with other

antihypertensive agents. Therefore, the dosage of diltiazem or the concomitant antihypertensives

may need to be adjusted when adding one to the other.

Paediatric population

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

recommended for use in children.

Method of administration

For oral administration

4.3

CONTRAINDICATIONS

Sick sinus syndrome except in the presence of a functioning ventricular pacemaker

Second- or third- degree AV block except in the presence of a functioning ventricular

pacemaker

Hypotension (less than 90 mmHg systolic)

Congestive heart failure

Severe bradycardia (below 40 bpm)

Concomitant use of dantrolene infusion (see Section 4.5)

Concomitant use of ivabradine (see Section 4.5)

Idiosyncrasy or hypersensitivity to diltiazem or any of the excipients listed under Section

Breastfeeding

Left ventricular failure with pulmonary congestion

New Zealand Data Sheet

Cardizem CD – Diltiazem Hydrochloride

cardizem-cd-ccdsv13-dsv17-20apr20

Page 4

Acute myocardial infarction and pulmonary congestion documented by X-ray on

admission.

4.4

SPECIAL WARNINGS AND PRECAUTIONS FOR USE

Calcium channel blocking agents, such as diltiazem, may be associated with mood changes,

including depression (see Section 4.5 and Section 4.8).

Like other calcium channel antagonists, diltiazem has an inhibitory effect on intestinal motility.

Therefore, it should be used with caution in patients at risk to develop an intestinal obstruction.

Cardiac Conduction

Close observation is necessary in patients with reduced left ventricular function, bradycardia (risk

of exacerbation) or with a first degree AV block detected on the electrocardiogram (risk of

exacerbation and rarely, of complete block).

Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node

recovery time, except in patients with sick sinus syndrome. This effect may rarely result in

abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-

degree AV block (nine of 2,111 patients, or 0.43%). Concomitant use of diltiazem with beta-

blockers or digitalis may result in additive effects on cardiac conduction (see Section 4.5). A

patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose

of 60 mg diltiazem hydrochloride.

Congestive Heart Failure

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations,

haemodynamic studies in humans with normal ventricular function have not shown a reduction in

cardiac index nor consistent negative effects on contractility (dp/dt). An acute study of oral

diltiazem in patients with impaired ventricular function (ejection fraction 24%

6%) showed

improvement in indices of ventricular function without significant decrease in contractile function

(dp/dt). Experience with the use of diltiazem in combination with beta-blockers in patients with

impaired ventricular function is limited. Caution should be exercised when using this

combination (see Section 4.5).

Hypotension

Decreases in blood pressure associated with diltiazem therapy may occasionally result in

symptomatic hypotension.

New Zealand Data Sheet

Cardizem CD – Diltiazem Hydrochloride

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Page 5

Acute Renal Failure

Cases of acute renal failure have been reported in patients using diltiazem at therapeutic dosages.

Patients at greater risk appear to have reduced left ventricular function, severe bradycardia or

severe hypotension.

Acute Hepatic Injury

Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase

and bilirubin have been observed in clinical studies. Such elevations were usually transient and

frequently resolved even with continued diltiazem treatment. In rare instances, significant

elevations in enzymes such as alkaline phosphatase, LDH, AST, ALT, and other phenomena

consistent with acute hepatic injury have been noted. These reactions tended to occur early after

therapy initiation (1 to 8 weeks) and have been reversible upon discontinuation of drug therapy.

The relationship to diltiazem is uncertain in some cases, but probable in some (see Section 4.8).

Dermatological Events

Dermatological events (see Section 4.8) may be transient and may disappear despite continued use

of diltiazem. However, skin eruptions progressing to erythema multiforme and/or exfoliative

dermatitis have also been infrequently reported. Should a dermatological reaction persist, the

drug should be discontinued.

Use in Diabetics

Diltiazem should be used with caution in patients suffering from diabetes. Like other calcium

channel blockers, diltiazem influences insulin secretion and its peripheral action by inhibiting

calcium influx into cells. In one study, increases in fasting and peak glucose levels were observed

after 2 to 6 months of diltiazem administration. Careful monitoring is necessary in patients with

latent or manifest diabetes mellitus due to a possible increase in blood glucose.

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

Controlled and uncontrolled studies suggest that concomitant use of diltiazem and beta-blockers is

usually well tolerated, but available data are not sufficient to predict the effects of concomitant

treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities (see

Section 4.5).

New Zealand Data Sheet

Cardizem CD – Diltiazem Hydrochloride

cardizem-cd-ccdsv13-dsv17-20apr20

Page 6

Administration of diltiazem concomitantly with propranolol in five normal volunteers resulted in

increased propranolol levels in all subjects and bioavailability of propranolol was increased by

approximately 50%. If combination therapy is initiated or withdrawn in conjunction with

propranolol, an adjustment in the propranolol dose may be warranted.

In contrast, there appears to be no effect on the pharmacokinetics of atenolol, a renally cleared

drug. In view of the known pharmacodynamic interactions between these classes of drugs, this

effect may be of clinical relevance.

Use with Amiodarone

Amiodarone should be used with caution with diltiazem particularly if there is suspicion of

underlying dysfunction of the sinus node, such as bradycardia or sick sinus syndrome or if there is

partial A-V block (see Section 4.5).

Concomitant Use of Digoxin

Diltiazem has been shown to increase serum digoxin concentrations and to modify its

pharmacokinetics (see Section 4.5). Patients with plasma digoxin levels in the upper therapeutic

range (1.5 to 2.5 ng/mL) may develop toxic plasma concentrations and side effects. Therefore,

digoxin plasma concentrations should be controlled 6 to 8 days after starting these drug

combinations, at which time new steady state conditions develop and the digoxin dose can be

reduced if there is evidence of toxicity.

Long Term Use

Data to support long term use or with doses higher than 360 mg/day are limited. Treatment at

doses above 360 mg/day does not offer increased efficacy, but is associated with a greater risk of

adverse reactions. Therefore treatment with doses exceeding 360 mg/day is not recommended.

Abrupt Withdrawal

The sudden withdrawal of diltiazem has been associated with severe angina in anginal patients.

Use in Hepatic or Renal Impairment

Increase of plasma concentrations of diltiazem may be observed in the elderly and in patients with

renal or hepatic insufficiency. The contraindications and precautions should be carefully

observed and close monitoring, particularly of heart rate, should be carried out at the beginning of

treatment.

Diltiazem is extensively metabolised by the liver and excreted by the kidneys and in bile. As with

any new drug given over prolonged periods, laboratory parameters should be monitored at regular

intervals. Diltiazem should be used with caution in patients with renal or hepatic impairment. In

subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem

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were associated with hepatic damage. In special subacute hepatic studies, oral studies of 125

mg/kg and higher in rats were associated with histological changes in the liver which were

reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with

hepatic changes; however, these changes were reversible with continued dosing.

Use in the Elderly

Administration of diltiazem to elderly patients (over or equal to 65 years of age) requires caution.

Plasma diltiazem concentrations can be increased in the elderly. The incidence of adverse

reactions is approximately 13% higher in this group. Those adverse reactions which occur more

frequently include: peripheral oedema, bradycardia, palpitation, dizziness, rash and polyuria.

Therefore, particular care in titration is advisable.

Paediatric Population

Safety and effectiveness in children have not been established. Therefore, diltiazem is not

recommended for use in children.

Effects on laboratory tests

No data available.

4.5

INTERACTION WITH OTHER MEDICINES AND OTHER FORMS OF INTERACTION

Due to the potential for additive effects, caution and careful titration are necessary in patients

receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or

conduction.

Diltiazem is metabolised by CYP3A4. A moderate (less than 2-fold) increase of diltiazem plasma

concentration in cases of co-administration with a stronger CYP3A4 inhibitor has been

documented. Diltiazem is also a CYP3A4 isoform inhibitor. Co-administration with other

CYP3A4 substrates may result in an increase in plasma concentration of either co-administered

drug. Co-administration of diltiazem with a CYP3A4 inducer may result in a decrease of

diltiazem plasma concentrations.

No pharmacokinetic interaction studies have been conducted with the Cardizem CD or SR

formulations. However, interactions reported with the conventional formulation are still relevant.

As with all drugs, care should be exercised when treating patients with multiple medications.

Diltiazem undergoes biotransformation by cytochrome P-450 mixed function oxidase. Co-

administration of diltiazem with other agents which follow the same route of biotransformation

may result in the competitive inhibition or induction of metabolism. This may lead to an

increased risk of adverse reactions.

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Dantrolene infusion

Lethal ventricular fibrillation is regularly observed in animals when intravenous verapamil and

dantrolene are administered concomitantly. The combination of a calcium channel antagonist and

dantrolene is therefore potentially dangerous.

Ciclosporin

Concomitant administration of diltiazem and ciclosporin has resulted in increased blood

ciclosporin concentrations and consequent ciclosporin-induced nephrotoxicity. Although further

study is needed, it has been suggested that diltiazem may interfere with metabolism of ciclosporin

via hepatic microsomal enzyme inhibition. The possibility that diltiazem may increase serum

ciclosporin concentrations should be considered if the drugs are used concomitantly. It is

recommended that the ciclosporin dose be reduced, renal function be monitored, circulating

ciclosporin levels be assayed and that the dose should be adjusted during combined therapy and

after its discontinuation.

Rifampicin

There is a risk of decreased diltiazem plasma levels after initiating therapy with rifampicin. The

patient should be carefully monitored when initiating or discontinuing rifampicin treatment.

Benzodiazepines (midazolam, triazolam)

Diltiazem significantly increases plasma concentration of midazolam and triazolam and prolongs

their half-life. Special care should be taken when prescribing short-acting benzodiazepines

metabolised by the CYP3A4 pathway in patients using diltiazem.

Corticosteroids (methylprednisolone)

Concomitant administration has resulted in the inhibition of methylprednisolone metabolism

(CYP3A4) and inhibition of P-glycoprotein. The patient should be monitored when initiating

methylprednisolone treatment. An adjustment in the dose of methylprednisolone may be

necessary.

Beta-blockers

Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem and beta-

blockers or digitalis is usually well tolerated, but available data are not sufficient to predict the

effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction

abnormalities.

Administration of diltiazem concomitantly with propranolol in five normal volunteers resulted in

increased propranolol levels in all subjects and bioavailability of propranolol was increased by

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approximately 50%. If combination therapy is initiated or withdrawn in conjunction with

propranolol, an adjustment in the propranolol dose may be warranted.

Due to the possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial

and atrio-ventricular conduction disturbances and heart failure (synergistic effect), combination

therapy with diltiazem and beta-blockers must only be used under close clinical and ECG

monitoring, particularly at the beginning of treatment.

An increased risk of depression has been reported when diltiazem is co-administered with beta-

blockers (see Section 4.8).

Digoxin

Concomitant use of diltiazem and digoxin may result in an additive effect on conduction.

Diltiazem has been shown to modify digoxin pharmacokinetics in healthy subjects, in patients

with cardiac insufficiency and in patients with chronic atrial fibrillation. Increases in plasma

digoxin concentrations ranged from 24 to 70%. The renal digoxin clearance was decreased from

86.9

18.3 to 62.8

15.4 mL/minute and digoxin elimination half-life was prolonged from 36.7

11.2 to 44.5

11.5 hours during conventional diltiazem co-administration. There is an increased

risk of bradycardia with this combination. Caution is required when digoxin is combined with

diltiazem, particularly in the elderly and when high doses are used.

H

2

antagonists (cimetidine, ranitidine)

Concomitant use may result in increased plasma diltiazem concentrations. Patients receiving

diltiazem concurrently with an H

antagonist should be carefully monitored when initiating or

discontinuing therapy with H

antagonists. An adjustment in diltiazem daily dose may be

necessary.

Concurrent administration of cimetidine produced an increase in single-dose diltiazem levels

(approximately 50% over control). The plasma levels of diltiazem's metabolite desacetyl

diltiazem were also increased.

Diazepam

Diazepam has been reported to cause a significant decrease in diltiazem plasma levels. The

average decrease in diltiazem concentration was between 20 and 30%. Three out of eight patients

showed decreases which were greater than 50%.

Carbamazepine

Concomitant use may result in increased circulating carbamazepine levels. It is recommended

that the plasma carbamazepine concentrations be assayed and that the dose should be adjusted if

necessary.

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Phenytoin

When co-administered with phenytoin, diltiazem may increase phenytoin plasma concentration.

It is recommended that phenytoin plasma concentrations be monitored.

Lithium

There is an increased risk of lithium-induced neurotoxicity.

Theophylline

Concomitant use results in an increase in circulating theophylline levels.

Ivabradine

Concomitant use with ivabradine is contraindicated due to the additional heart rate lowering effect

of diltiazem (see Section 4.3).

Alpha-blockers

Concomitant treatment with alpha-blockers may produce or aggravate hypotension. The

combination of diltiazem with an alpha-blocker should only be considered with the strict

monitoring of blood pressure due to the risk of increased antihypertensive effects.

Amiodarone

Sinus arrest and a life-threatening low cardiac output state developed when amiodarone was

added to a regimen of diltiazem and a diuretic. It has been suggested that diltiazem and

amiodarone have additive adverse effects on sinus node function and myocardial contractility (see

Section 4.4). There is an increased risk of bradycardia with this combination. Caution is required

when amiodarone is combined with diltiazem, particularly in the elderly and when high doses are

used.

Short and long acting nitrates

Increased hypotensive effects and faintness may be seen due to additive vasodilatating effects. In

patients treated with calcium channel antagonists, the addition of nitrate derivatives should only

be carried out at gradually increasing doses.

Anaesthetic agents

Additive haemodynamic depressive effects are found when calcium channel blockers are

combined with inhalation anaesthetic agents such as halothane, isoflurane or enflurane. These

effects are related both to the anaesthetic concentration and to the dose of the calcium channel

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blocker. Depression of cardiac contractility, conductivity and automaticity, as well as the vascular

dilatation associated with anaesthetics may be potentiated by calcium channel blockers.

Prior to general anaesthesia, the anaesthetist must be informed of ongoing diltiazem treatment.

Statins

Diltiazem is an inhibitor of CYP3A4 and has been shown to significantly increase the AUC of

some statins. The risk of myopathy and rhabdomyolysis due to statins metabolised by CYP3A4

may be increased with concomitant use of diltiazem. When possible, a non CYP3A4-metabolised

statin should be used together with diltiazem, otherwise close monitoring for signs and symptoms

of a potential statin toxicity is required.

Administration of a single 20 mg dose of simvastatin in 10 healthy volunteers, after 2 weeks of

120 mg of Cardizem SR twice daily, resulted in a significantly (p

<

0.05) increased mean peak

serum concentration of simvastatin by 3.6 fold and simvastatin acid by 3.7 fold, the AUC by 4.8

fold for simvastatin and the elimination half-life by 2.3 fold. There was no change in the time to

peak concentration curve for simvastatin and simvastatin acid. Concomitant use of diltiazem with

simvastatin should be used with caution, particularly at the higher end of the dosing range.

In another 10 volunteer study, the co-administration of 120 mg of Cardizem SR twice daily with

lovastatin resulted in a 3-4 times increase in mean lovastatin AUC and C

versus lovastatin

alone. No change in pravastatin AUC and C

was observed during Cardizem SR co-

administration. The effects of statins on the pharmacokinetic parameters of diltiazem have not

been determined.

Cilostazol

Concomitant administration has resulted in the inhibition of cilostazol metabolism (CYP3A4).

Diltiazem has been shown to increase cilostazol exposure and to enhance its pharmacological

activity.

Other Antiarrhythmic Agents

Since diltiazem has antiarrhythmic properties, its concomitant use with other antiarrhythmic

agents is not recommended (additive risk of increased cardiac adverse effects). Such combination

should only be used under close clinical and ECG monitoring.

Aspirin/Acetylsalicylates

The concomitant administration of aspirin/acetylsalicylates with diltiazem should be undertaken

with caution because of the increased risk of bleeding due to potential additive effect on platelet

aggregation.

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Other Antiplatelet Drugs

In a pharmacodynamic study, diltiazem was shown to inhibit platelet aggregation. Although the

clinical significance of this finding is unknown, potential additive effects when used with

antiplatelet drugs should be considered.

Grapefruit Juice

Grapefruit juice may increase diltiazem exposure. Patients who consume grapefruit juice should

be monitored for increased effects of diltiazem. Grapefruit juice should be avoided if an

interaction is suspected.

X-ray Contrast Media

Cardiovascular effects of an intravenous bolus of an ionic X-ray contrast media, such as

hypotension, may be increased in patients treated with diltiazem. Special caution is required in

patients who concomitantly receive diltiazem and X-ray contrast media.

4.6

FERTILITY, PREGNANCY AND LACTATION

Pregnancy (Category C)

Reproduction studies have been conducted in mice, rats and rabbits. Administration of high doses

has resulted in embryo and foetal lethality. These doses, in some studies, have been reported to

cause skeletal abnormalities. In the prenatal/postnatal studies there was some reduction in early

individual pup weights and survival rates. There was an increased incidence of stillbirths at high

doses.

There are no well controlled studies in pregnant women. Also, diltiazem is a calcium channel

blocker and drugs listed in this class carry the potential for foetal hypoxia associated with

maternal hypotension. Diltiazem is therefore not recommended during pregnancy, as well as in

women of child-bearing potential not using effective contraception.

Breast-feeding

Diltiazem levels were measured in both serum and milk in lactating women. Samples were taken

simultaneously on the fourth day of the treatment with diltiazem, 60 mg four times a day. The

peak level in milk was as high as 200 ng/mL and was almost the same as that in the serum. These

data show that diltiazem is freely diffusible in milk but it is not known whether it is harmful to the

newborn. Therefore, breastfeeding while taking this drug should be avoided. If use of diltiazem

is considered medically essential, an alternative method of infant feeding should be instituted.

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Fertility

No data available.

4.7

EFFECTS ON ABILITY TO DRIVE AND USE MACHINES

On the basis of reported adverse drug reactions, i.e. dizziness (common), malaise (common), the

ability to drive and use machines could be altered. However, no studies have been performed.

4.8

UNDESIRABLE EFFECTS

Serious adverse reactions have been rare in studies carried out to date, but it should be recognised

that patients with impaired ventricular function and cardiac conduction abnormalities have been

usually been excluded from these studies.

The following table presents the most common adverse reactions reported in placebo-controlled

angina and hypertension trials in patients receiving Cardizem CD up to 360 mg with rates in

placebo patients shown for comparison.

Table 1 - DOUBLE BLIND PLACEBO CONTROLLED HYPERTENSION AND ANGINA TRIALS (with

the CD formulation)

ADVERSE REACTION

CARDIZEM CD

N=607

PLACEBO

N=301

Headache

Dizziness

Bradycardia

AV block first degree

Oedema

ECG abnormality

Asthenia

5.4%

3.0%

3.3%

3.3%

2.6%

1.6%

1.8%

5.0%

3.0%

1.3%

1.3%

2.3%

1.7%

In clinical trials of diltiazem as CD capsules, tablets and SR capsules involving 3,200 patients, the

following undesirable effects were reported. They are presented in the following table by system

organ class (SOC) and ranked under heading of frequency.

The following CIOMS frequency rating is used:

Very common: ≥10%; Common: ≥1 and <10%; Uncommon: ≥0.1 and <1%; Rare: ≥0.01 and

<0.1%; Very rare: <0.01%; Not known: cannot be estimated from available data.

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System organ class

Frequency and symptom

Metabolism and nutritional

disorders

Uncommon: hyperglycaemia, hyperuricaemia

Nervous system disorders

Common: headache (4.9)%, dizziness (3.5%), asthenia (2.7%)

Uncommon: abnormal dreams, amnesia, depression, gait abnormality, hallucinations,

insomnia, nervousness, paraesthesia, personality change, somnolence, tinnitus, tremor

Eye disorders

Uncommon: amblyopia, eye irritation

Cardiac disorders

Common: first-degree AV block (2.2%), second or third degree AV block, bradycardia (1.6%),

palpitations

Uncommon: angina, arrhythmia, bundle branch block, congestive heart failure, ECG

abnormalities, hypotension, syncope, tachycardia, ventricular extrasystoles

Vascular disorders

Common: flushing (1.5%)

Uncommon: orthostatic hypotension

Respiratory disorders

Uncommon: dyspnoea

Gastrointestinal disorders

Common: nausea (1.4%), dyspepsia (1.2%), constipation, gastric pain

Uncommon: anorexia, diarrhoea, dry mouth, dysgeusia, thirst, vomiting, weight increase

Hepato-biliary disorders

Uncommon: hepatic enzyme increase (AST, ALT, LDH, ALP), (in rare cases clinical hepatitis

has been reported, reversible upon discontinuation of diltiazem; see Section 4.4)

Skin and subcutaneous tissue

disorders

Common: rash (1.3%), erythema

Uncommon: petechiae, photosensitivity, pruritus, urticaria

Musculoskeletal and connective

tissue disorders

Uncommon: CPK increase, muscle cramp, osteoarticular pain

Renal and urinary disorders

Uncommon: nocturia, polyuria

Reproductive system and breast

disorders

Uncommon: impotence, sexual difficulties

General disorders and

administration site conditions

Very Common: lower limb oedema,

Common: oedema (4.6%), malaise

Uncommon: epistaxis, nasal congestion

POST-MARKETING EXPERIENCE

The following postmarketing events have been reported infrequently in patients receiving

diltiazem: mood changes including depression, hyperglycaemia, extrapyramidal syndrome, sino-

atrial block, congestive heart failure, sinus arrest, cardiac arrest (asystole), photosensitivity,

hepatitis, alopecia, gynaecomastia, vasculitis, musculo-cutaneous reactions such as simple

erythema or occasionally desquamative erythema with or without fever, angioneurotic oedema,

symptoms of vasodilation (such as flushing, lower limb oedema, sweating), erythema multiforme

(including rare cases of Steven-Johnson’s syndrome), exfoliative dermatitis, acute generalised

exanthematous pustular dermatitis or pustulosis, orthostatic hypotension, malaise, gastric pain,

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extrapyramidal symptoms, gingival hyperplasia, haemolytic anaemia, increased bleeding time,

leukopenia, purpura, retinopathy and thrombocytopenia. Very rare cases of toxic epidermal

necrolysis have also been reported. In addition, events such as myocardial infarction have been

observed which are not readily distinguishable from the natural history of the disease in these

patients. A number of well-documented cases of rash, characterised as leukocytoclastic vasculitis,

have been reported. However, a definitive cause and effect relationship between these events and

diltiazem therapy is yet to be established. 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 adverse 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.

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.

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

collapse and acute kidney injury, sinus bradycardia with or without isorhythmic dissociation,

sinus arrest, cardiac arrest, 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.

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. Based on the known pharmacological effects of

diltiazem and/or reported clinical experiences, the following measures may be considered:

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Bradycardia

Administer atropine (0.60 to 1.0 mg). If there is no response to vagal blockade administer

isoprenaline cautiously.

High-Degree AV Block

Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac

pacing.

Cardiac Failure

Administer inotropic agents (isoprenaline, dopamine, or dobutamine) and diuretics.

Hypotension

Vasopressors (eg. dopamine or noradrenaline acid tartrate).

Actual treatment and dosage should depend on the severity of the clinical situation and the

judgement and experience of the treating physician.

Symptoms and signs of overdose may be delayed due to the controlled release properties of the

product, so patients should be kept under observation for at least 24 hours.

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

POISON (0800 764766).

5

PHARMACOLOGICAL PROPERTIES

Diltiazem hydrochloride (CAS 33286-22-5) is a calcium ion influx inhibitor (slow channel

blocker or calcium antagonist). Its molecular formula is C

S.HCl and it has the

following structure:

HCl

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It has a molecular weight of 450.98.

5.1

PHARMACODYNAMIC PROPERTIES

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

C08D B01.

The therapeutic effects achieved with diltiazem hydrochloride are believed to be related to its ability

to inhibit the influx of calcium ions during membrane depolarisation of cardiac and vascular smooth

muscle.

Mechanisms of Action

Diltiazem hydrochloride produces its antihypertensive effects primarily by relaxation of vascular

smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of

blood pressure reduction is related to the degree of hypertension; thus hypertensive individuals

experience an antihypertensive effect, whereas there is only a modest fall in blood pressure in

normotensives.

Haemodynamic and Electrophysiologic Effects

Like some other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular

conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the

intact animal, prolongation of the AH interval can be seen at higher doses.

In man, diltiazem prevents spontaneous and ergometrine provoked coronary artery spasm. It

causes a decrease in peripheral vascular resistance and a modest fall in blood pressure and, in

exercise tolerance studies in patients with ischaemic heart disease, reduces the heart rate-blood

pressure product for any given work load. Studies to date, primarily in patients with good

ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output,

ejection fraction and left ventricular end diastolic pressure have not been affected. Increased heart

failure has, however, been reported in occasional patients with pre-existing impairment of

ventricular function. There are as yet few data on the interaction of diltiazem and beta-blockers in

patients with poor ventricular function. Resting heart rate is usually slightly reduced by diltiazem.

Diltiazem produces antihypertensive effects both in the supine and standing positions. Postural

hypotension is infrequently noted upon suddenly assuming an upright position. No reflex

tachycardia is associated with the chronic antihypertensive effects. Diltiazem decreases vascular

resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease

or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited

while maximum achievable systolic pressure is usually reduced. Heart rate at maximum exercise

does not change or is slightly reduced. Chronic therapy with diltiazem produces no change or an

increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone

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axis has been observed. Diltiazem reverses the renal and peripheral effects of angiotensin II.

Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased

urinary output and natriuresis without a change in urinary sodium/potassium ratio.

Intravenous diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional

and effective refractory periods by approximately 20%. In a study involving single oral doses of

300 mg of conventional diltiazem hydrochloride in six normal volunteers, the average maximum

PR prolongation was 14% with no instances of greater than first-degree AV block. Diltiazem-

associated prolongation of the AH interval is not more pronounced in patients with first-degree

heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle

length (up to 50% in some cases).

Chronic oral administration of diltiazem hydrochloride to patients in doses of up to 540 mg/day

has resulted in small increases in PR interval but has not usually produced abnormal prolongation

(see Section 4.4).

5.2

PHARMACOKINETIC PROPERTIES

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass

effect, giving an absolute bioavailability (compared to intravenous administration) of about 40%.

Diltiazem undergoes extensive metabolism in which 2% to 4% of the unchanged drug appears in

the urine.

In vitro

ligand binding studies show diltiazem is 70% to 80% bound to plasma proteins.

Competitive

in vitro

ligand binding studies have also shown diltiazem binding is not altered by

therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic

acid, or warfarin. The plasma elimination half-life following single or multiple drug

administration is approximately 3.0 to 4.5 hours. Desacetyl diltiazem is also present in the plasma

at levels of 10% to 20% of the parent drug and is 25% to 50% as potent a coronary vasodilator as

diltiazem. Minimum therapeutic plasma levels of diltiazem appear to be in the range of 50 - 200

ng/mL.

There is a departure from linearity when dose strengths are increased; the half-life is slightly

increased with dose. A study that compared patients with normal hepatic function to patients with

cirrhosis found an increase in half-life and a 69% increase in bioavailability in the hepatically

impaired patients. A single study in patients with severely impaired renal function showed no

difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal

function.

No studies have been conducted in patients with gastrointestinal disease. As with other modified

release oral preparations, patients with diarrhoea or colonic disease may have impaired absorption

due to a shortened gastric transit time.

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Cardizem CD Capsules

When compared to a diltiazem tablet at steady-state, more than 95% of drug is absorbed from the

Cardizem CD capsule formulation. A single 360 mg dose of the capsule results in detectable

plasma levels within 2 hours and peak plasma levels between 10 and 14 hours.

When Cardizem CD was co-administered with a high fat content breakfast, the absorption of

diltiazem was delayed but the extent of diltiazem absorption and total bioavailability were not

affected. Dose-dumping does not occur. The apparent elimination half-life after single or

multiple dosing is 5 to 8 hours. A departure from linearity similar to that seen with Cardizem

tablets and Cardizem SR capsules is observed. As the dose of Cardizem CD capsules is increased

from a daily dose of 120 mg to 240 mg, there is an increase in the area-under-the curve of 2.7

times. When the dose is increased from 240 mg to 360 mg there is an increase in the area-under-

the curve of 1.6 times.

A single capsule of Cardizem CD 360 mg was found to be bioequivalent to two Cardizem CD 180

mg capsules.

No information is available regarding the pharmacokinetics and bioavailability of diltiazem in the

CD or SR capsule form in patients with hepatic or renal failure, or in elderly hypertensive

patients.

5.3

PRECLINICAL SAFETY DATA

No further relevant information other than that which is already included in the other sections of

the Data Sheet

6

PHARMACEUTICAL PARTICULARS

6.1

LIST OF EXCIPIENTS

The 120 mg capsules contain the following inactive ingredients: brilliant blue FCF, castor oil,

ethylcellulose, fumaric acid, gelatin, methacrylic acid copolymers, purified talc, colloidal

anhydrous silica, simethicone, stearic acid, sugar spheres, titanium dioxide, tributyl acetylcitrate

and white beeswax.

The 180 and 240 mg capsules contain the following inactive ingredients: fumaric acid, purified

talc, colloidal anhydrous silica, nonpareil seeds (PI 1366), white beeswax, ethylcellulose, castor

oil, stearic acid, tributyl acetylcitrate, simethicone, and methacrylic acid copolymers (Eudragit RS

30D and Eudragit RL 30D) and gelatin. In addition the following dyes are used: brilliant blue

FCF, titanium dioxide and black iron oxide.

The 360 mg capsules contain the following inactive ingredients: nonpareil seeds (PI 3631),

povidone, sodium lauryl sulfate, diethyl phthalate, purified talc, methacrylic acid copolymers

New Zealand Data Sheet

Cardizem CD – Diltiazem Hydrochloride

cardizem-cd-ccdsv13-dsv17-20apr20

Page 20

(Eudragit RS 30D and Eudragit RL 30D), tributyl acetylcitrate, simethicone, titanium dioxide,

brilliant blue FCF and gelatin.

6.2

INCOMPATIBILITIES

Not applicable.

6.3

SHELF LIFE

Cardizem CD 120 mg, 180 mg and 240 mg capsules have a shelf life of 36 months from date of

manufacture.

Cardizem CD 360 mg capsules have a have a shelf life of 24 month from date of manufacture.

6.4

SPECIAL PRECAUTIONS FOR STORAGE

Protect from light and moisture. Store below 25°C.

6.5

NATURE AND CONTENTS OF CONTAINER

Cardizem CD 120 mg capsules are packaged in plastic high density polyethylene bottles in packs

of 7*, 30* or 100* capsules, or in PVC/PE/PVDC/Al foil blister packs of 7*, 30* or 100*

capsules.

Cardizem CD 180 mg and 240 mg capsules are packaged in plastic high density polyethylene

bottles in packs of 7*, 30* or 100* capsules, or in PVC/PE/PVDC/Al foil blister packs of 7*, 28*,

30 or 100* capsules.

Cardizem CD 360 mg capsules are packaged in plastic high density polyethylene bottles in packs

of 7* or 30* capsules, or in PVC/PE/PVDC/Alu foil blister packs of 7*, 10*, 28*, 30* or 100*

capsules.

*Denotes presentations not available in New Zealand

6.6

SPECIAL PRECAUTIONS FOR DISPOSAL

No special requirements

7

MEDICINE SCHEDULE

Prescription Only Medicine

New Zealand Data Sheet

Cardizem CD – Diltiazem Hydrochloride

cardizem-cd-ccdsv13-dsv17-20apr20

Page 21

8

SPONSOR

sanofi-aventis new zealand limited

Level 8, 56 Cawley Street, Ellerslie

Auckland New Zealand

Toll Free Number (medical information): 0800 283 684

Email: medinfo.australia@sanofi.com

9

DATE OF FIRST APPROVAL

120 mg capsules: 19 October 1995

180 mg and 240 mg capsules: 29 July 1993

360 mg capsules: 11 November 1999

10

DATE OF REVISION OF THE TEXT

20 April 2020

SUMMARY TABLE OF CHANGES

Section changed

Summary of new information

Acute renal failure warning added

Update to section to include acute kidney injury

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