Consumer medicine information

Cardizem CD capsules and Cardizem tablets

Diltiazem hydrochloride

BRAND INFORMATION

Brand name

Cardizem CD Extended release capsules

Active ingredient

Diltiazem hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Cardizem CD capsules and Cardizem tablets.

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.

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.

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 764 766), 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
  • 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
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


BRAND INFORMATION

Brand name

Cardizem CD Extended release capsules

Active ingredient

Diltiazem hydrochloride

Schedule

S4

 

1 Name of Medicine

Cardizem (diltiazem hydrochloride) 60 mg film coated tablets.

6.7 Physicochemical Properties

Chemical structure.

Diltiazem hydrochloride is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist). Its molecular formula is C22H26N2O4S.HCl and it has the following structure:
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. It has a molecular weight of 450.98.

CAS number.

CAS 33286-22-5.

2 Qualitative and Quantitative Composition

Each tablet of Cardizem contains 60 mg diltiazem hydrochloride.
Diltiazem hydrochloride is a white to off white crystalline powder with a bitter taste. It is freely soluble in water, methanol and chloroform.

Excipients with known effect.

Lactose monohydrate and methyl hydroxybenzoate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Film coated tablet.
Cardizem 60 mg tablets are clear coated, light yellow, round double (13/32" or 1.03 cm) convex tablets with characteristic direct compression speckle. The word "Marion" is engraved on one side while the other side is scored and engraved with 1772.

5 Pharmacological Properties

5.1 Pharmacodynamic Properties

Pharmacotherapeutic group: Calcium channel blocker, Benzothiazepine derivatives, ATC code C08D B01.
The therapeutic benefits achieved with diltiazem are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarisation of cardiac and vascular smooth muscle.

Mechanism of action.

Although precise mechanisms of its antianginal actions are still being delineated, diltiazem is believed to act in the following ways.

1. Vasospastic angina.

Diltiazem has been shown to be a potent dilator of coronary arteries both epicardial and subendocardial. Spontaneous and ergometrine induced coronary artery spasm are inhibited by diltiazem.

2. Exertional angina.

Diltiazem has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand and increase oxygen supply. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal exercise work loads and by dilating coronary arteries.
In animal models, diltiazem interferes with the slow inward (depolarising) current in excitable tissue. It causes excitation contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscle and dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischaemic and nonischaemic models and are accompanied by dose dependent decreases in systemic blood pressure and decreases in peripheral resistance.

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 workload. 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. There are as yet few data on the interaction of diltiazem and beta-blockers. Resting heart rate is usually unchanged or slightly reduced by diltiazem.
Intravenous diltiazem hydrochloride in doses of 20 mg prolongs AH conduction time and A-V node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of 300 mg of diltiazem in six normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first degree A-V 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 in doses of up to 240 mg/day has resulted in small increases in PR interval but has not usually produced abnormal prolongation. There were, however, three instances of second degree A-V block and one instance of third degree A-V block in a group of 959 chronically treated patients.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Diltiazem is absorbed from the tablet formulation to about 80% of a reference capsule and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to intravenous dosing) of about 40%. Diltiazem undergoes extensive hepatic metabolism in which 2% to 4% of the unchanged drug appears in the urine. In vitro binding studies show diltiazem is 70% to 80% bound to plasma proteins. Competitive ligand binding studies have also shown diltiazem binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylic acid or warfarin. Single oral doses of 30 to 120 mg of diltiazem result in detectable plasma levels within 30 to 60 minutes and peak plasma levels two to three hours after drug administration. The plasma elimination half-life following single or multiple drug administration is approximately 3.5 hours. Desacetyldiltiazem 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. Therapeutic blood levels of diltiazem appear to be in the range of 50 to 200 nanogram/mL. There is a departure from dose linearity when single doses above 60 mg are given; a 120 mg dose gave blood levels three times that of the 60 mg dose. There is no information about the effect of renal or hepatic impairment on excretion or metabolism of diltiazem.

5.3 Preclinical Safety Data

Genotoxicity.

No data available.

Carcinogenicity.

No data available.

4 Clinical Particulars

4.1 Therapeutic Indications

Patients with moderate to severe angina pectoris due to atherosclerotic coronary artery disease or coronary artery spasm (vasospastic angina).

4.3 Contraindications

Sick sinus syndrome except in the presence of a functioning ventricular pacemaker.
Second or third degree A-V block except in the presence of a functioning ventricular pacemaker.
Hypotension (less than 90 mmHg systolic).
Severe congestive heart failure.
Severe bradycardia (below 40 bpm).
Concomitant use of dantrolene infusion (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Concomitant use of ivabradine (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).
Idiosyncrasy or hypersensitivity to diltiazem or any of the excipients listed, see Section 6.1 List of Excipients.
Breastfeeding.
Left ventricular failure with pulmonary congestion.
Patients with 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 Interactions with Other Medicines and Other Forms of Interactions; Section 4.8 Adverse Effects (Undesirable Effects)).
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 (six of 1,243 patients or 0.48%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg diltiazem.

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). Experience with the use of diltiazem alone or in combination with beta-blockers in patients with impaired ventricular function is very limited. Caution should be exercised when using the drug in such patients (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Hypotension.

Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.

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.

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 have been reversible upon discontinuation of drug therapy. The relationship to diltiazem is uncertain in most cases, but probable in some (see Section 4.8 Adverse Effects (Undesirable Effects)).

Dermatological events.

Dermatological events (see Section 4.8 Adverse Effects (Undesirable Effects)) may be transient and may disappear despite continued use of diltiazem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have been infrequently reported. Should dermatological reactions 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 Interactions with Other Medicines and Other Forms of Interactions).
Administration of diltiazem hydrochloride concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately 50%. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted.

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 AV block (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions).

Concomitant use of digoxin.

Diltiazem has been shown to increase serum digoxin concentrations and to modify its pharmacokinetics (see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). Patients with plasma digoxin levels in the upper therapeutic range (1.5 to 2.5 nanogram/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 of diltiazem (longer than 1 year) with doses higher than 240 mg/day is limited. Therefore the long-term treatment with doses exceeding 240 mg/day is not recommended.

Abrupt withdrawal.

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

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 hydrochloride is extensively metabolised by the liver and excreted by the kidneys and in bile. As with any 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 were associated with hepatic damage. In special subacute hepatic studies, oral doses 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 (see Section 4.2 Dose and Method of Administration).

Paediatric use.

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 Interactions with Other Medicines and Other Forms of Interactions

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 coadministration with a stronger CYP3A4 inhibitor has been documented. Diltiazem is also a CYP3A4 isoform inhibitor. Coadministration with other CYP3A4 substrates may result in an increase in plasma concentration of either coadministered drug. Coadministration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.
As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem undergoes biotransformation by cytochrome P450 mixed function oxidase. Coadministration 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.

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.

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.

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.

Beta-blockers.

Controlled and uncontrolled studies suggest that concomitant diltiazem and beta-blockers or digitalis is usually well tolerated. Available data are not sufficient, however, to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities.
Administration of diltiazem hydrochloride concomitantly with propranolol in five normal volunteers resulted in increased propranolol levels in all subjects and bioavailability was increased 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), sinoatrial and atrioventricular 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 coadministered with beta-blockers (see Section 4.8 Adverse Effects (Undesirable Effects)).

Digoxin.

Concomitant use of diltiazem and digoxin may result in 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 diltiazem coadministration. 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.

H2-antagonists (cimetidine, ranitidine).

Concomitant use may result in increased plasma diltiazem concentrations. Patients receiving diltiazem concurrently with an H2-antagonist should be carefully monitored when initiating or discontinuing therapy with H2-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, desacetyldiltiazem, 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.

Phenytoin.

When coadministered with phenytoin, diltiazem may increase phenytoin plasma concentration. It is recommended that the 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 Contraindications).

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 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 on myocardial contractility (see Section 4.4 Special Warnings and Precautions for Use). 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 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 Cardizem CD with simvastatin should be used with caution, particularly at the higher end of the dosing range.
In another 10 volunteer study, the coadministration of 120 mg of Cardizem SR twice daily with lovastatin resulted in a 3-4 times increase in mean lovastatin AUC and Cmax versus lovastatin alone.
No change in pravastatin AUC and Cmax was observed during Cardizem SR coadministration. 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.

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

Effects on fertility.

No data available.
(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.
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 nanogram/mL and was almost the same as that in 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.

4.8 Adverse Effects (Undesirable Effects)

More common reactions.

In clinical trials of diltiazem in anginal patients, the most common events (i.e. greater than 1%) were: oedema (2.4%), headache (2.1%), nausea (1.9%), AV block (1.6%), dizziness (1.5%), rash (1.3%), asthenia (1.2%), urticaria, palpitations, constipation, dyspepsia, gastric pain, malaise, erythema, flushing, lower limb oedema and lightheadedness.
Lower limb oedema has been reported as very common.

Less common reactions.

In addition, the following events were reported infrequently (less than 1%).

Cardiovascular.

Angina, arrhythmia, AV block (first degree), AV block second or third degree (see Section 4.4 Special Warnings and Precautions for Use), bradycardia, bundle branch block, congestive heart failure, ECG abnormality, flushing, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.

Nervous system.

Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paraesthesia, personality change, somnolence, tinnitus, tremor.

Gastrointestinal.

Anorexia, constipation, diarrhoea, dry mouth, dysgeusia, dyspepsia, hepatic enzymes increase (AST, ALT, LDH, ALP), (in rare cases, clinical hepatitis has been reported, reversible upon discontinuation of diltiazem; see Section 4.4 Special Warnings and Precautions for Use), thirst, vomiting, weight increase.

Dermatological.

Petechiae, photosensitivity, pruritus, urticaria.

Other.

Amblyopia, CPK increase, dyspnoea, epistaxis, eye irritation, hyperglycaemia, hyperuricaemia, impotence, muscle cramp, nasal congestion, nocturia, osteoarticular pain, polyuria, sexual difficulties.

Postmarketing 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 and toxic epidermal necrolysis), exfoliative dermatitis, acute generalised exanthematous pustular dermatitis, orthostatic hypotension, malaise, gastric pain, 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 cannot yet be established. Bronchospasm (including asthma aggravation) has also been reported.

Reporting of suspected adverse reactions.

Reporting suspected adverse reactions after registration of the medicinal product is important. It allows continued monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions at http://www.tga.gov.au/reporting-problems.

4.2 Dose and Method of Administration

For oral administration.

Angina.

Dosage must be adjusted to each patient's needs. Starting with 30 mg four times daily before meals and at bedtime, dosage should be increased gradually (given in divided doses three or four times daily) at one to two day intervals until optimum response is obtained. Although individual patients may respond to any dosage level, the average optimum dosage range appears to be 180 to 240 mg/day. The maximum recommended dose is 360 mg daily. There are no available data concerning dosage requirements in patients with impaired renal or hepatic function. If the drug must be used in such patients, titration should be carried out with particular caution.

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 Special Warnings and Precautions for Use).

Use in patients with renal or hepatic impairment.

Diltiazem should be used with caution in patients with renal or hepatic impairment (see Section 4.4 Special Warnings and Precautions for Use).

Concomitant use with other antianginal and antihypertensive agents.

Sublingual glyceryl trinitrate.

May be taken as required to abort acute anginal attacks during diltiazem therapy. Diltiazem may be safely coadministered with short and long acting nitrates but there have been no controlled studies to evaluate the antianginal effectiveness of this combination.

Beta-blockers.

See Section 4.4 Special Warnings and Precautions for Use.

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.

4.7 Effects on Ability to Drive and Use Machines

No specific studies have been conducted to assess the direct effect of Cardizem on the ability to drive and use machines. However, adverse effects of Cardizem include dizziness which could affect the ability to drive or use machines. See Section 4.8 Adverse Effects (Undesirable Effects).

4.9 Overdose

The oral LD50 in mice and rats ranged from 415 to 740 mg/kg and from 560 to 810 mg/kg, respectively. The intravenous LD50 in these species was 60 and 38 mg/kg, respectively. The oral LD50 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 atrioventricular 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.

Bradycardia.

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

High degree A-V block.

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

Cardiac failure.

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

Hypotension.

Vasopressors (e.g. dopamine or noradrenaline acid tartrate).
Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.
For information on the management of overdose, contact the Poisons Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Cardizem tablets also contain lactose monohydrate, microcrystalline cellulose, hypromellose, colloidal anhydrous silica, magnesium stearate, methyl hydroxy benzoate, colouring (Quinoline Yellow CI 47005 and Sunset Yellow FCF CI 15985) and a film coating (Opadry YS-5-7044 Clear and methyl hydroxybenzoate).

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.

6.3 Shelf Life

In Australia, information on the shelf life can be found on the public summary of the Australian Register of Therapeutic Goods (ARTG). The expiry date can be found on the packaging.

6.4 Special Precautions for Storage

Protect from light and moisture. Store below 30°C.

6.5 Nature and Contents of Container

Cardizem 60 mg tablets are supplied in high density polyethylene bottles with a child resistant closures in packs of 90 tablets.

6.6 Special Precautions for Disposal

In Australia, any unused medicine or waste material should be disposed of by taking to your local pharmacy.

Summary Table of Changes