Consumer medicine information

Diltiazem AN Tablets

Diltiazem hydrochloride

BRAND INFORMATION

Brand name

Diltiazem AN Tablets

Active ingredient

Diltiazem hydrochloride

Schedule

S4

 

Consumer medicine information (CMI) leaflet

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

What is in this leaflet

This leaflet answers some common questions about DILTIAZEM AN. 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 DILTIAZEM AN 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 AN is used for

The name of your medicine is DILTIAZEM AN. It contains the active ingredient called diltiazem hydrochloride.

DILTIAZEM AN belongs 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.

DILTIAZEM AN is used to prevent angina.

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.

Your doctor may have prescribed DILTIAZEM AN for another reason. Ask your doctor if you have any questions about why DILTIAZEM AN has been prescribed for you.

There is no evidence that DILTIAZEM AN is addictive.

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

Before You Take DILTIAZEM AN

When you must not take it

Do not use DILTIAZEM AN if:

  1. 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
  2. you are pregnant, or intend to become pregnant.
    DILTIAZEM AN may affect your developing baby if you take it during pregnancy.
  3. you are breast-feeding or intend to breast-feed.
    DILTIAZEM AN passes into breast milk and may affect your baby.

Do not use DILTIAZEM AN if the packaging is torn or shows signs of tampering.

Do not use DILTIAZEM AN 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 using DILTIAZEM AN, 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 use it

Tell your doctor if:

  1. you have allergies to
  • any other medicines
  • any other substances such as foods, preservatives or dyes.
  1. you are pregnant or intend to become pregnant.
    DILTIAZEM AN should not be used during pregnancy.
  2. you are breast-feeding or planning to breast-feed.
    Your doctor will discuss the risks and benefits of using DILTIAZEM AN during breastfeeding. A decision will have to be made whether to discontinue breastfeeding or discontinue therapy taking into consideration the importance of the medicine.
  3. you have, or have had, the following medical conditions:
  • Abnormal heart beat rhythm
  • hypotension (low blood pressure)
  • Heart attack or other heart-related complications
  • Impaired renal (kidney) or hepatic (liver) function
  • Diabetes

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 DILTIAZEM AN. These include:

  • Dantrolene (a muscle relaxant)
  • Some other medicines for your heart or high blood pressure (eg. beta blockers, digoxin, amiodarone, nitrates)
  • Cyclosporin, 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)
  • Carbamazepine (for bipolar disorder or epilepsy)
  • Lithium (for bipolar disorder)
  • Theophylline (for asthma and other breathing problems)
  • Certain drugs used to treat prostate problems
  • 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

These medicines may be affected by DILTIAZEM AN, or may affect how well it works. 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 avoid while taking DILTIAZEM AN.

How to take DILTIAZEM AN

How much to take

DILTIAZEM AN is usually taken 3 - 4 times a day. Take the prescribed dose as directed by your doctor.

A lower dosage may be required in elderly patients (over 65 years old).

Follow all directions given to you by your doctor and pharmacist carefully. They may differ from the information contained in this leaflet.

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

How to take it

Swallow the tablets whole with a glass of water.

When to take it

Take DILTIAZEM AN tablets at the same time each day as directed by your doctor.

How long to take it

Take DILTIAZEM AN for as long as your doctor tells you to.

Do not stop taking DILTIAZEM AN suddenly because this can bring on an attack of angina.

If you forget to take it

If 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 as you would normally.

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

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

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

If you take too much (overdose)

Immediately telephone your doctor or Poisons Information Centre (telephone 13 11 26), or go to casualty at your nearest hospital, if you think that you or anyone else may have taken too much DILTIAZEM AN. Do this even if there are no signs of discomfort or poisoning. You may need urgent medical attention.

If you take too much DILTIAZEM AN, you may feel dizzy and light-headed, feel pain in your left arm or chest or notice your heart beating very slowly. If any of these occur you should get medical attention immediately.

While you are taking DILTIAZEM AN

Things you must do

Use DILTIAZEM AN 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.

Tell your doctor if you continue to have angina attacks or if they become more frequent while you are using DILTIAZEM AN.

Tell all doctors, dentists and pharmacists who are treating you that you are taking DILTIAZEM AN.

Tell your doctor or pharmacist that you are taking DILTIAZEM AN if you are about to be started on any new medicines.

Things you must not do

Do not use it to treat any other complaints unless your doctor says to.

Do not give this medicine to anyone else, even if their symptoms seem similar to yours.

As mentioned previously, 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 DILTIAZEM AN affects you.

DILTIAZEM AN may cause dizziness and fainting in some patients, especially when you first start to use it. Make sure you know how you react to DILTIAZEM AN 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 DILTIAZEM AN.

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

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 DILTIAZEM AN.

DILTIAZEM AN helps most people with angina, but it may have unwanted effects in a few people.

All medicines can have side effects. Sometimes they are serious, 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 are the more common side effects of DILTIAZEM AN. These side effects are usually mild.

If any of the following happen, stop taking DILTIAZEM AN and tell your doctor immediately or go to casualty at your nearest hospital:

  • 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.

These are very serious side effects. You may need urgent medical attention or hospitalisation. These 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 don’t understand anything in this list.

Do not be alarmed by this list of possible side effects. You may not experience any of them.

After taking DILTIAZEM AN

Storage

Keep your tablets in their blister pack until it is time to take them.

If you take the tablets out of their blister pack they may not keep well.

Keep DILTIAZEM AN in a cool, dry place where it stays below 25°C. Do not store it, or any other medicine, in a bathroom or near a sink. Do not leave it in the car or on window sills.

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 DILTIAZEM AN, or the tablets have passed their expiry date, ask your pharmacist what to do with any tablets left over.

Product description

What it looks like

DILTIAZEM AN 60 mg tablets are white, film coated, capsule shaped and scored with one face embossed DL/60.

DILTIAZEM AN 60 mg tablets are available in blister packs (AUST R 184100) and bottle packs (AUST R 184098) of 90 tablets.

Ingredients

DILTIAZEM AN tablets contain 60 mg of the active ingredient diltiazem hydrochloride.

Other Ingredients:

  • dried aluminium hydroxide
  • hydrogenated castor oil
  • lactose
  • magnesium stearate
  • methacrylic acid copolymer
  • Opadry white Y-1-7000B (hypromellose, titanium dioxide, macrogol 400, indigo carmine CI73015)
  • purified talc

DILTIAZEM AN does not contain sucrose, gluten, tartrazine or any other azo dyes.

Name and Address of the Sponsor

Amneal Pharma Australia Pty Ltd
12 River St
South Yarra, Vic, 3141
Australia

Date of Preparation

May 2015

Doc ID: 56.AN.M.2.0

BRAND INFORMATION

Brand name

Diltiazem AN Tablets

Active ingredient

Diltiazem hydrochloride

Schedule

S4

 

Name of the medicine

Diltiazem hydrochloride.

Excipients.

Lactose, hydrogenated castor oil, dried aluminium hydroxide, methacrylic acid copolymer, talc, magnesium stearate, opadry white Y-1-7000B (hypromellose, titanium dioxide, macrogol 400, indigo carmine).

Description

Chemical name: (2S, 3S)-5-(2-dimethylaminoethyl)-2, 3, 4, 5-tetrahydro-2-(4-methoxyphenyl)-4- oxo-1, 5-benzothiazepin-3-yl acetate. Molecular formula: C22H26N2O4S, HCl. MW: 450.98. CAS: 33286-22-5. It is a white to off white crystalline powder with a bitter taste, soluble in water, methanol and chloroform.

Actions.

Calcium ion influx inhibitor (slow channel blocker or calcium antagonist).

Pharmacology

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.

Mechanisms 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 workloads 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 electrophysiological effects.

Like 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 diseases, 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 and 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 in doses of 20 mg prolongs AH conduction time and atrioventricular node functional and effective refractory period 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 atrioventricular 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 atrioventricular block and one instance of third degree atrioventricular block in a group of 959 chronically treated patients.

Pharmacokinetics.

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 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; an 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.

Indications

Moderate to severe angina pectoris due to atherosclerotic coronary artery disease or coronary artery spasm (vasospastic angina).

Contraindications

Sick sinus syndrome except in the presence of a functioning ventricular pacemaker.
Second or third degree atrioventricular 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 Interactions with Other Medicines).
Breastfeeding.
Left ventricular failure with pulmonary congestion.
Patients with acute myocardial infarction and pulmonary congestion documented by X-ray on admission.

Precautions

Cardiac conduction.

Close observation is necessary in patients with reduced left ventricular function, bradycardia or with a first degree A-V block.
Diltiazem AN prolongs atrioventricular 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 atrioventricular block (six of 1,243 patients or 0.48%). Concomitant use of Diltiazem AN with β-blockers or digitalis may result in additive effects on cardiac conduction (see also Interactions with Other Medicines). A patient with Prinzmetal's angina developed periods of asystole (2 to 5 seconds) after a single dose of 60 mg Diltiazem AN.

Congestive heart failure.

Although Diltiazem AN 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 AN 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 also Interactions with Other Medicines).

Hypotension.

Decreases in blood pressure associated with Diltiazem AN 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 Adverse Effects).

Impaired hepatic or renal function.

Plasma diltiazem concentrations can be increased in patients with renal or hepatic insufficiency. Diltiazem AN (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. 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 AN 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.

Dermatological events.

(See Adverse Effects.) May be transient and may disappear despite continued use of Diltiazem AN. 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 AN should be used with caution in patients suffering from diabetes. Like other calcium channel blockers, Diltiazem AN 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 AN administration.

Concomitant administration with β-blockers.

Controlled and uncontrolled studies suggest that concomitant use of diltiazem and beta-blockers or digitalis is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities (see also Interactions with Other Medicines).
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 AN particularly if there is suspicion of underlying dysfunction of the sinus node, such as bradycardia or sick sinus syndrome or if there is partial atrioventricular block (see Interactions with Other Medicines).

Concomitant uses with digoxin.

Diltiazem AN has been shown to increase serum digoxin concentrations and to modify its pharmacokinetics (see Interactions with Other Medicines). 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 AN (longer than one year) with doses higher than 240 mg/day are limited. Therefore the long-term treatment with doses exceeding 240 mg/day is not recommended.

Abrupt withdrawal.

The sudden withdrawal of Diltiazem AN has been associated with severe angina.

Paediatric use.

Safety and effectiveness in children have not been established.

Use in pregnancy.

(Category C)
Reproduction studies have been conducted in mice, rats and rabbits. Administration of high doses has resulted in embryo and fetal 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 increased incidence of stillbirths at high doses.
There are no well controlled studies in pregnant women. Also, Diltiazem AN is a calcium channel blocker and drugs listed in this class carry the potential for foetal hypoxia associated with maternal hypotension. Accordingly, Diltiazem AN is not recommended during pregnancy, as well as in women of childbearing potential not using effective contraception.

Use in lactation.

Diltiazem AN levels were measured in both serum and milk in lactating women. Samples were taken simultaneously on the fourth day of the treatment with Diltiazem AN, 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 AN is freely diffusible in milk but it is not known whether it is harmful to the newborn infant. Therefore, breastfeeding while taking Diltiazem AN is contraindicated. If use of Diltiazem AN is considered medically essential, an alternative method of infant feeding should be instituted.

Use in the elderly.

Administration of diltiazem to elderly patients (65 years of age or over) 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 Dosage and Administration.)

Interactions

Due to the potential for additive effects, caution and careful titration are necessary in patients receiving Diltiazem AN concomitantly with other agents known to affect cardiac contractility and/or conduction.
As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem AN undergoes biotransformation by cytochrome P450 mixed function oxidase. Coadministration of Diltiazem AN 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.

Cyclosporin.

Concomitant administration of diltiazem and cyclosporin has resulted in increased blood cyclosporin concentrations and consequent cyclosporin induced nephrotoxicity. Although further study is needed, it has been suggested that diltiazem may interfere with metabolism of cyclosporin via hepatic microsomal enzyme inhibition. The possibility that diltiazem may increase serum cyclosporin concentrations should be considered if the drugs are used concomitantly. Downward titration of cyclosporin 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.

Beta-blockers.

Controlled and uncontrolled studies suggest that concomitant Diltiazem AN 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 AN (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, combination therapy with diltiazem and beta-blockers must only be used under close clinical and ECG monitoring, particularly at the beginning of treatment.

Digoxin.

Concomitant use of Diltiazem AN and digoxin may result in additive effect on conduction. Diltiazem AN 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 AN 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 AN levels (approximately 50% over control). The plasma levels of Diltiazem AN's metabolite, desacetyldiltiazem were also increased.

Diazepam.

Diazepam has been reported to cause a significant decrease in Diltiazem AN 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.

Lithium.

There is an increased risk of lithium induced neurotoxicity.

Theophylline.

Concomitant use results in an increase in circulating theophylline levels.

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 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 Precautions). 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.

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 capsule 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.

Other antiarrhythmic agents.

Since diltiazem has antiarrhythmic properties, its concomitant use with other antiarrhythmic agents is not recommended. Such combination should only be used under close clinical and ECG monitoring.

Adverse 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%), A-V block (1.6%), dizziness (1.5%), rash (1.3%), asthenia (1.2%), urticaria and lightheadedness.

Less common reactions.

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

Cardiovascular.

Angina, arrhythmia, A-V block (first degree), A-V block second or third degree (see Precautions), 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, mild elevations of AST, ALT, LDH, and alkaline phosphatase (in rare cases, clinical hepatitis has been reported, reversible upon discontinuation of diltiazem; see Precautions), 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. The following postmarketing events have been reported infrequently in patients receiving diltiazem: 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), exfoliative dermatitis, acute generalised exanthematous pustular dermatitis, sinoatrial block, 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 is yet to be established.

Dosage and 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.

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 Precautions).

Concomitant use with other antianginal and antihypertensive agents.

Sublingual glyceryl trinitrate may be taken as required to abort acute anginal attacks during Diltiazem AN therapy.

β-blockers.

See Precautions.

Concomitant treatment with antihypertensives.

Diltiazem AN has an additive antihypertensive effect when used with other antihypertensive agents. Therefore, the dosage of Diltiazem AN or the concomitant antihypertensives may need to be adjusted when adding one to the other.

Overdosage

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.
Events observed following diltiazem overdose included bradycardia, hypotension, heart block and cardiac failure. 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 or haemodialysis. Based on the known pharmacological effects of diltiazem and/or reported clinical experiences, the following measures may be considered.

Bradycardia.

Administer atropine (0.6 to 1 mg). If there is no response to vagal blockade, administer isoprenaline cautiously.

High degree atrioventricular block.

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

Cardiac failure.

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

Hypotension.

Vasopressors (dopamine or noradrenaline acid tartrate).
Actual treatment should depend on the severity of the clinical situation and the judgement and experience of the treating physician.
Contact the Poisons Information Centre on 131 126 for advice on the management of an overdose.

Presentation

Tablets, 60 mg (white, capsule shaped, film coated, scored, marked DL/60): 90's (PVC/ PVDC/ aluminium blister pack, AUST R 184100).

Storage

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

Poison Schedule

S4.