Consumer medicine information

Diltiazem Sandoz Tablets

Diltiazem hydrochloride

BRAND INFORMATION

Brand name

Diltiazem Sandoz Tablets

Active ingredient

Diltiazem hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

Please read this leaflet carefully before you start using Diltiazem Sandoz Tablets.

WHAT IS IN THIS LEAFLET

This leaflet answers some common questions about Diltiazem Sandoz.

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 this medicine against the benefits they expect it will have for you.

If you have any concerns about taking this medicine, ask your doctor or pharmacist.

Keep this leaflet with the medicine.

You may need to read it again.

WHAT DILTIAZEM SANDOZ IS USED FOR

This medicine is used to prevent angina.

Angina is a pain or uncomfortable feeling in the chest, often spreading to the arms and neck, and sometimes the shoulders and back. This may be caused by too little blood and oxygen getting to the heart. Angina is usually brought on by exercise or stress.

It contains the active ingredient diltiazem hydrochloride.

Diltiazem belongs to a group of medicines called calcium channel blockers.

It works by opening up blood vessels, thereby increasing the blood flow and allowing more blood (and oxygen) to reach the heart.

Ask your doctor if you have any questions about why this medicine has been prescribed for you.

Your doctor may have prescribed it for another reason.

This medicine is not addictive.

This medicine is available only with a doctor's prescription.

BEFORE YOU TAKE DILTIAZEM SANDOZ

When you must not take it

Do not take this medicine if you have an allergy to:

  • diltiazem hydrochloride, the active ingredient, or to any of the other ingredients listed at the end of this leaflet under PRODUCT DESCRIPTION.

Some of the symptoms of an allergic reaction may include:

  • asthma, wheezing or shortness of breath
  • wheezing or difficulty breathing
  • swelling of the face, lips, tongue or other parts of the body
  • rash, itching or hives on the skin
  • fainting.

Do not take this medicine if you have or have had any of the following conditions:

  • sick sinus syndrome (unless you have a working pacemaker)
  • second or third degree AV block (unless you have a working pacemaker)
  • low blood pressure (hypotension)
  • severe congestive heart failure
  • severe bradycardia (slow heart rate)
  • heart attack
  • pulmonary congestion (excessive amount of fluid in the lungs).

Do not take this medicine with ivabradine.

Combination with ivabradine may cause additional heart rate lowering effect of diltiazem to ivabradine.

Do not take this medicine if you are pregnant or intend to become pregnant.

It may affect your developing baby if you take it during pregnancy.

Do not breastfeed if you are taking this medicine.

The active ingredient in Diltiazem Sandoz passes into breast milk and there is a possibility that your baby may be affected.

Do not take this medicine after the expiry date printed on the pack or if the packaging is torn or shows signs of tampering.

If it has expired or is damaged, return it to your pharmacist for disposal.

If you are not sure whether you should start taking this medicine, talk to your doctor.

Before you start to take it

Tell your doctor if you have allergies to any other medicines, foods, preservatives or dyes.

Tell your doctor if you are pregnant or intend to become pregnant.

Diltiazem Sandoz should not be used during pregnancy.

Tell your doctor 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.

Tell your doctor if you have or have had any of the following medical conditions:

  • abnormal heartbeat rhythm
  • hypotension (low blood pressure)
  • heart attack or other heart-related problems
  • kidney or liver problems
  • diabetes.

If you have not told your doctor about any of the above, tell him/her before you start taking Diltiazem Sandoz.

Taking other medicines

Tell your doctor or pharmacist if you are taking any other medicines, including any that you get without a prescription from your pharmacy, supermarket or health food shop.

Some medicines and Diltiazem Sandoz may interfere with each other. These include:

  • beta-blockers, such as propranolol or atenolol, medicines used to treat high blood pressure or other heart problems
  • certain medicines used to treat prostate problems
  • medicines used to treat irregular heartbeats, such as amiodarone
  • medicines used to treat reflux and stomach ulcers, such as cimetidine or ranitidine
  • diazepam, a medicine used to treat anxiety, depression or alcohol withdrawal
  • rifampicin, a medicine used to treat tuberculosis
  • carbamazepine, a medicine used for a variety of conditions (such as epilepsy, mania, bipolar mood disorder or trigeminal neuralgia)
  • rimonabant, an appetite-reducing medicine
  • lithium, a medicine used to treat some types of depression
  • theophylline, a medicine used to treat asthma
  • cyclosporin, a medicine used in patients who have received organ transplants or to treat certain problems with the immune system
  • medicines used to treat high cholesterol, such as simvastatin or atorvastatin
  • inhaled anaesthetics, such as isoflurane, enflurane or halothane (for surgery)
  • dantrolene, a muscle-relaxant medicine.
  • benzodiazepines or medicines used as sedatives or to treat anxiety, such as midazolam, triazolam
  • corticosteroids, such as methylprednisolone, prednisone, cortisone.

These medicines may be affected by Diltiazem Sandoz or may affect how well it works. You may need different amounts of your medicines, or you may need to take different medicines.

Your doctor and pharmacist have more information on medicines to be careful with or avoid while taking this medicine.

HOW TO TAKE DILTIAZEM SANDOZ

Follow all directions given to you by your doctor or pharmacist carefully.

They may differ from the information contained in this leaflet.

If you do not understand the instructions, ask your doctor or pharmacist for help.

How much to take

Ask your doctor or pharmacist if you are unsure of the correct dose for you.

They will tell you exactly how much to take.

Follow the instructions they give you.

If you take the wrong dose, Diltiazem Sandoz may not work as well and your problem may not improve.

Diltiazem Sandoz is usually taken three or four times daily.

How to take it

Swallow the tablets whole with a full glass of water. Do not chew them.

When to take Diltiazem Sandoz

Take your medicine at about the same time each day.

Taking it at the same time each day will have the best effect. It will also help you remember when to take it.

How long to take Diltiazem Sandoz

Continue taking your medicine for as long as your doctor tells you.

This medicine helps to control your condition, but does not cure it. It is important to keep taking your medicine even if you feel well.

If you forget to take it

Take your dose as soon as you remember, and continue to take it as you would normally.

If it is almost time for your next dose, skip the dose you missed and take your next dose when you are meant to.

If you are taking this medicine for angina, do not suddenly stop taking it, as this can cause severe angina for one or two days.

Do not take a double dose to make up for the dose that you missed.

This may increase the chance of you getting an unwanted side effect.

If you are not sure what to do, ask your doctor or pharmacist.

If you have trouble remembering to take your medicine, ask your pharmacist for some hints.

If you take too much (overdose)

Immediately telephone your doctor or the Poisons Information Centre (telephone 13 11 26) for advice, or go to Accident and Emergency at the nearest hospital, if you think that you or anyone else may have taken too much Diltiazem Sandoz. Do this even if there are no signs of discomfort or poisoning.

You may need urgent medical attention.

Symptoms of an overdose may include:

  • light-headedness
  • dizziness
  • slow or irregular heartbeat
  • pain in the left arm and/or chest.

WHILE YOU ARE TAKING DILTIAZEM SANDOZ

Things you must do

If you are about to be started on any new medicine, remind your doctor and pharmacist that you are taking Diltiazem Sandoz.

Tell any other doctors, dentists, and pharmacists who treat you that you are taking this medicine.

If you are going to have surgery, tell the surgeon or anaesthetist that you are taking this medicine.

It may affect other medicines used during surgery.

If you become pregnant while taking this medicine, tell your doctor immediately.

If you are taking this medicine for angina, tell your doctor if you continue to have angina attacks or if they become more frequent.

Keep all of your doctor's appointments so that your progress can be checked.

Your doctor may do some tests from time to time to make sure the medicine is working and to prevent unwanted side effects.

Things you must not do

Do not take Diltiazem Sandoz to treat any other complaints unless your doctor tells you to.

Do not give your medicine to anyone else, even if they have the same condition as you.

Do not stop taking your medicine or lower the dosage without checking with your doctor.

Stopping your medicine suddenly may bring on an angina attack. Your doctor may want you to gradually reduce the amount you are taking before stopping completely.

Things to be careful of

Be careful driving or operating machinery until you know how Diltiazem Sandoz affects you.

This medicine may cause dizziness or light-headedness in some people, especially after the first dose. If you have any of these symptoms, do not drive, operate machinery or do anything else that could be dangerous.

Be careful when drinking alcohol while you are taking this medicine.

If you drink alcohol, dizziness or light-headedness may be worse.

If you feel light-headed, dizzy or faint when getting out of bed or standing up, get up slowly.

Standing up slowly, especially when you get up from bed or chairs, will help your body get used to the change in position and blood pressure. If this problem continues or gets worse, talk to your doctor.

Be careful not to overdo physical activities when you first start taking this medicine.

You may feel better when you start taking this medicine, but you will need time to improve your physical fitness.

Drinking grapefruit juice may increase the effects of diltiazem.

SIDE EFFECTS

Tell your doctor or pharmacist as soon as possible if you do not feel well while you are taking Diltiazem Sandoz.

All medicines can have side effects. Sometimes they are serious, most of the time they are not. You may need medical attention if you get some of the side effects.

Do not be alarmed by the following lists of side effects. You may not experience any of them.

Ask your doctor or pharmacist to answer any questions you may have.

Tell your doctor or pharmacist 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 are the more common side effects of the medicine. Mostly, these are mild.

Tell your doctor immediately if you notice any of the following:

  • feeling 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.

The above list includes serious side effects that may require medical attention. Serious side effects are rare.

Other side effects not listed above may also occur in some people.

Tell your doctor or pharmacist 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 DILTIAZEM SANDOZ

Storage

Keep your medicine in the original container.

If you take it out of its original container it may not keep well.

Keep your medicine in a cool dry place where the temperature stays below 25°C.

Do not store Diltiazem Sandoz or any other medicine in the bathroom or near a sink. Do not leave it on a window sill or in the car.

Heat and dampness can destroy some medicines.

Keep it where 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 this medicine or the expiry date has passed, ask your pharmacist what to do with any medicine that is left over.

PRODUCT DESCRIPTION

What it looks like

Diltiazem Sandoz 60mg - white, round, biconvex tablets with a score notch on one side.

Available in blisters and bottles of 90 tablets.

Ingredients

Active ingredients:

  • Diltiazem Sandoz 60mg - 60mg diltiazem hydrochloride.

Inactive ingredients:

  • hydrogenated castor oil
  • lactose
  • povidone
  • macrogol 6000
  • microcrystalline cellulose
  • sodium starch glycollate
  • colloidal anhydrous silica
  • magnesium stearate
  • hypromellose
  • stearic acid
  • titanium dioxide.

This medicine does not contain sucrose, gluten, tartrazine or any other azo dyes.

Supplier

Diltiazem Sandoz is supplied in Australia by:

Sandoz Pty Ltd
ABN 60 075 449 553
54 Waterloo Road,
Macquarie Park, NSW 2113
Australia
Tel: 1800 634 500

This leaflet was revised in October 2015.

Australian Register Number
60mg tablets: AUST R 60838 (blisters)
60mg tablets: AUST R 62646 (bottles)

BRAND INFORMATION

Brand name

Diltiazem Sandoz Tablets

Active ingredient

Diltiazem hydrochloride

Schedule

S4

 

1 Name of Medicine

Diltiazem hydrochloride.

6.7 Physicochemical Properties

Diltiazem hydrochloride is a white to off white crystalline powder with a bitter taste, soluble in water, methanol and chloroform.
The chemical name of Diltiazem hydrochloride is (2S,3S)-5-(2-dimethylaminoethyl)-2,3,4,5-tetrahydro-2-(4-methoxyphenyl)-4-oxo-1,5-benzothiazepin-3-yl acetate hydrochloride (MW: 450.98).

Chemical structure.

Its chemical structure is:

CAS number.

33286-22-5.

2 Qualitative and Quantitative Composition

Each Diltiazem Sandoz 60 mg film-coated tablets contains 60 mg diltiazem hydrochloride.
Excipient with known effect: lactose monohydrate.
For the full list of excipients, see Section 6.1 List of Excipients.

3 Pharmaceutical Form

Diltiazem Sandoz 60 mg tablets are white, round, biconvex film-coated tablets, scored on one side.

5 Pharmacological Properties

Diltiazem is a calcium ion influx inhibitor (slow channel blocker or calcium antagonist).
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.

5.1 Pharmacodynamic Properties

Mechanism of action.

Although the 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 increase 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 electrophysiological 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 atrial-His (A-H) interval can be seen at higher doses.
In humans, 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 end diastolic pressure have not been affected. There are as yet few data on the interaction of diltiazem and β-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 AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of diltiazem 300 mg 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 in doses of up to 240 mg/day has resulted in small increases in PK interval but has not usually produced abnormal prolongation. There were, however, three instances of second degree atrioventricular block and one instance of third degree atrioventricular block in a group of 959 chronically treated patients.

Clinical trials.

No data available.

5.2 Pharmacokinetic Properties

Diltiazem 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 diltiazem 30 to 120 mg 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 or 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

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 AV 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).
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.
Concomitant use of ivabradine.

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 (6 of 1,243 patients or 0.48%). Concomitant use of diltiazem with β-blockers or digitalis may result in additive effects on cardiac conduction (also see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions). A patient with Prinzmetal 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 β-blockers in patients with impaired ventricular function is very limited. Caution should be exercised when using the drug in such patients (also 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 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 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 two to six 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 β-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities (also 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 by 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 sinus node, such as bradycardia or sick sinus syndrome or if there is partial atrioventricular block (also 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 six to eight 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 one year) with doses higher than 240 mg/day are limited. Therefore 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 the bile. As with any drug given over long periods, laboratory parameters should be monitored at regular intervals. The drug should be used with caution in patients with impaired renal or hepatic function. 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 (≥ 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 (also see Section 4.2 Dose and Method of Administration).

Paediatric use.

Safety and effectiveness in children have not been established.

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 that 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 cyclosprin 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.
Downward titration of ciclosporin dose may be required to minimise the risk of nephrotoxic potential.

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 concentrations of midazolam and triazolam and prolongs their half-life. Special care should be taken when prescribing short acting benzodiazepines metabolized by the CYP3A4 pathway in patients using diltiazem.

β-blockers.

Controlled and uncontrolled studies suggest that concomitant use of diltiazem and β-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 of propranolol was increased approximately 50%. If combination therapy is initiated or withdrawn in conjunction with propranolol, an increase in the propranolol dose may be warranted.
Due to the possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sinoatrial and AV conduction disturbances and heart failure (synergistic effect), combination therapy with diltiazem and β-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 β-blockers (see Section 4.8 Adverse Effects (Undesirable Effects)).

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. Increase 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/min and digoxin elimination half-life was prolonged from 36.7 ± 112 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 increase plasma diltiazem concentrations. Patients receiving diltiazem concurrently with 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 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 to ivabradine (see Section 4.3 Contraindications).

Rimonabant.

Coadministration with diltiazem results in an increase in serum rimonabant levels.

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 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 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 diltiazem sustained release capsules 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 dosage range.
In another 10 volunteer study, the coadministration of 120 mg of diltiazem sustained release capsules 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 diltiazem sustained release capsules 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 received 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 perinatal/ 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 not recommended during pregnancy, as well as in women of childbearing potential not using effective contraception.
Australian categorisation definition of Category C. Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Accompanying texts should be consulted for further details.
 Diltiazem levels were measured in both serum and milk in breastfeeding 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 infant.
Therefore, breastfeeding while taking diltiazem is contraindicated. If use of diltiazem is 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%), atrioventricular 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 light headedness.
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, first degree AV block, second or third degree AV block (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, mood changes, depression, gait abnormality, hallucinations, insomnia, nervousness, paraesthesia, personality change, somnolence, tinnitus, tremor.

Gastrointestinal.

Anorexia, constipation, diarrhoea, dry mouth, dysgeusia, dyspepsia, gastric pain, mild elevations of alkaline phosphatase, hepatic enzymes increase (AST, ALT, ALP and LDH) (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, erythema, photosensitivity, pruritus, urticaria.

Other.

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

Post-marketing experience.

The following postmarketing events have been reported infrequently in patients receiving diltiazem: mood changes (including depression), hyperglycaemia, extrapyramidal syndrome, sinoatrial block, congestive heart failure, sinus arrest, cardiac arrest (systole), photosensitivity, hepatitis, alopecia, gynaecomastia, vasculitis, musculocutaneous 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 Stevens-Johnson 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, leucopenia, 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 leucocytoclastic 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 suspected adverse effects.

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

Dosage.

Angina.

Dosage must be adjusted to each patient's needs. Starting with 30 mg four times daily, 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 daily. 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.

Dosage adjustment.

Renal impairment.

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

Hepatic impairment.

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

Elderly.

Pharmacokinetics of diltiazem in elderly patients has not been fully elucidated. Preliminary results in elderly patients (> 65 years old) suggest that a lower dosage might be required in this age group (also 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.

Prophylactic nitrate 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

The effects of this medicine on a person's ability to drive and use machines were not assessed as part of its registration.

4.9 Overdose

The oral LD50 values in mice and rats range from 415 to 740 mg/kg and from 560 to 810 mg/kg respectively. The intravenous LD50 values in these species were 60 and 38 mg/kg respectively. The oral LD50 value 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 humans 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.

Symptoms.

The clinical effects of acute overdose can involve pronounced hypotension possibly leading to collapse, sinus bradycardia, with or without isorhythmic dissociation, sinus arrest, cardiac arrest, heart block, cardiac failure, and atrioventricular conduction disturbances.

Treatment.

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 gastric lavage. Diltiazem does not appear to be removed by peritoneal dialysis 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 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.

Administer vasopressors (dopamine or noradrenaline acid tartate).
Actual treatment and dosage should depend on the severity of the clinical situation and the judgement and experience of the treating physician.
For information on the management of overdose, contact the Poison Information Centre on 13 11 26 (Australia).

7 Medicine Schedule (Poisons Standard)

S4.

6 Pharmaceutical Particulars

6.1 List of Excipients

Hydrogenated castor oil, lactose monohydrate, povidone 25, macrogol 6000, microcrystalline cellulose, sodium starch glycollate, colloidal anhydrous silica, magnesium stearate, hypromellose, stearic acid, titanium dioxide.

6.2 Incompatibilities

Incompatibilities were either not assessed or not identified as part of the registration of this medicine.
For information on interactions with other medicines and other forms of interactions, see Section 4.5 Interactions with Other Medicines and Other Forms of Interactions.

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

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

6.5 Nature and Contents of Container

Diltiazem Sandoz 60 mg tablets are packaged in blisters and bottles of 90 tablets.
Not all presentations may be marketed in Australia.

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