ADIZEM-XL 240 mg prolonged release capsules

Ireland - English - HPRA (Health Products Regulatory Authority)

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Active ingredient:
Diltiazem hydrochloride
Available from:
Mundipharma Pharmaceuticals Limited
ATC code:
C08DB; C08DB01
INN (International Name):
Diltiazem hydrochloride
Dosage:
240 milligram(s)
Pharmaceutical form:
Prolonged-release capsule
Prescription type:
Product subject to prescription which may be renewed (B)
Therapeutic area:
Benzothiazepine derivatives; diltiazem
Authorization status:
Marketed
Authorization number:
PA1688/001/006
Authorization date:
1994-12-16

pil-clean

Package Leaflet: Information for the user

Adizem

®

-XL 120 mg, 180 mg, 240 mg and 300 mg prolonged-release capsules

Diltiazem hydrochloride

Read all of this leaflet carefully before you start taking this medicine because it contains important

information for you

Keep this leaflet. You may need to read it again.

If you have any further questions, ask your doctor or pharmacist.

This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if

their signs of illness are the same as yours.

If you get any of the side effects talk to your doctor. This includes any possible side effects not listed in

this leaflet. See section 4.

What is in this leaflet:

What Adizem-XL capsules are and what they are used for

What you need to know before you take Adizem-XL capsules

How to take Adizem-XL capsules

Possible side effects

How to store Adizem-XL capsules

Contents of the pack and other information

1.

What Adizem-XL capsules are and what they are used for

These capsules have been prescribed for you to treat angina (chest pain caused by a reduction of oxygen to

the heart muscle) or high blood pressure (hypertension). They contain the active ingredient diltiazem.

Diltiazem belongs to a group of medicines called calcium antagonists. Calcium antagonists help more blood

to reach the heart and reduce blood pressure. The other ingredients of Adizem-XL capsules are listed in

section 6 of this leaflet.

Adizem-XL capsules are designed to work properly over 24 hours. If the capsules are crushed or

chewed, the entire 24 hour dose may be absorbed rapidly into your body. This can be dangerous,

causing serious problems such as an overdose.

2.

What you need to know before you take Adizem-XL capsules

Do not take Adizem-XL capsules if you:

are allergic (hypersensitive) to diltiazem or any of the other ingredients of the capsules (see section 6

‘Further Information’);

have a slow or irregular heart beat;

have heart failure (which can cause shortness of breath or ankle swelling);

have heart problems other than angina and hypertension;

are pregnant, might become pregnant or think you might be pregnant;

are breastfeeding;

are taking dantrolene (a muscle relaxant);

are allergic to peanuts or soya.

Children should not take these capsules

Warnings and precautions

Talk to your doctor or pharmacist before taking these tablets if you:

have liver or kidney problems as your doctor may monitor you more closely;

have porphyria (a rare disease of the blood pigments);

have bowel problems.

Other medicines and Adizem-XL capsules

Please tell your doctor or pharmacist if you are taking, have recently taken or might take any other

medicines, including medicines obtained without a prescription. If you take Adizem-XL capsules with some

other medicines, the effect of the Adizem-XL capsules or the other medicine may be changed.

Tell your doctor or pharmacist if you are taking:

any other medicines for high blood pressure, such as beta blockers (for example atenolol), diuretics

(for example bendrofluazide) or ACE inhibitors (examples include captopril and enalapril);

medicines known as alpha blockers, which you may be taking to treat high blood pressure or prostate

disorders (for example prazosin);

any medicines which may cause low blood pressure or slow heart beat (for example aldesleukin to

treat cancer of the kidneys, or antipsychotics to treat mental and behavioural disorders);

ivabradine to treat angina;

anti-arrhythmic medicines to treat an irregular or rapid heart beat (for example digoxin, amiodarone

or beta-blockers);

cilostazol to treat intermittent claudication (a condition that causes leg pain due to a restriction in

blood to the muscles);

medicines known as statins to reduce cholesterol levels in your blood (examples include simvastatin,

atorvastatin or lovastatin);

medicines known as H2 antagonists to treat stomach ulcers, indigestion or heartburn, such as

cimetidine or ranitidine;

carbamazepine or phenytoin to treat seizures, fits or convulsions;

medicines known as benzodiazepines to treat anxiety or help you sleep (examples include

midazolam or triazolam);

medicines known as barbiturates to either treat fits or to help you sleep (examples include

phenobarbital or primidone);

antidepressants known as tricyclic antidepressants (e.g. amitriptyline or imipramine) or lithium;

rifampicin to treat tuberculosis;

ciclosporin, sirolimus or tacrolimus to prevent organ transplant rejection or treat other immune

system disorders;

a specific type of medicine known as protease inhibitors to treat HIV (examples include atazanavir

or ritonavir);

dantrolene (a muscle relaxant);

theophylline to treat breathing problems such as asthma;

medicines known as nitrate derivatives to treat angina or high blood pressure (examples include

glyceryl trinitrate or isosorbide mononitrate);

medicines for inflammation or allergies, known as steroids (for example methylprednisolone).

Anaesthetics and Adizem-XL capsules

If you are having a general anaesthetic, tell your doctor that you are taking these capsules.

Adizem-XL capsules with food, drink and alcohol

Do not take these capsules at the same time as an alcoholic drink.

Pregnancy, breastfeeding and fertility

Do not take Adizem-XL capsules if you are pregnant, likely to become pregnant or are breastfeeding.

Ask your doctor or pharmacist for advice before taking any medicine.

Driving and using machines

These capsules may cause a number of side effects such as dizziness and a general feeling of being unwell.

These could affect your ability to drive or use machinery (see section 4 for a full list of side effects) and are

usually most noticeable when you start taking the capsules, or when changing to a higher dose. If you are

affected you should not drive or operate machinery.

Adizem-XL capsules contain soya oil

If you are allergic to peanuts or soya do not take these capsules.

3.

How to take Adizem-XL capsules

Always take Adizem-XL capsules exactly as your doctor has told you. The label on your medicine will tell

you how many capsules to take and how often.

Adults (over 18 years of age)

The usual starting dose is one 240 mg capsule every 24 hours. However, if you are elderly then your doctor

will probably suggest a lower starting dose of one 120 mg capsule every 24 hours. Your doctor will decide

how many capsules you should take.

Children

Children should not take these capsules.

Do not exceed the dose recommended by your doctor. You should check with your doctor or pharmacist if

you are not sure.

Swallow your capsules whole with a glass of water. Do not chew or crush the capsules.

You should take your capsules every 24 hours. For instance, if you take a capsule at 8 o’clock in the

morning, you should take your next capsule at 8 o’clock the next morning.

If you take more Adizem-XL capsules than you should or if someone accidentally swallows your

capsules

Call your doctor or hospital straight away. People who have taken an overdose may become very unwell, feel

faint, have a slow heart beat and lose consciousness. They may need emergency treatment in hospital. When

seeking medical attention make sure that you take this leaflet and any remaining capsules with you to show to

the doctor.

If you forget to take Adizem-XL capsules

If you remember within 4 hours of the time your capsule was due, take your capsule straight away. Take

your next capsule at your normal time. If you are more than 4 hours late, please call your doctor or

pharmacist for advice. Do not take a double dose to make up for a forgotten capsule.

If you stop taking Adizem-XL capsules

You should not stop taking these capsules unless your doctor tells you to. If you want to stop taking your

capsules, discuss this with your doctor first.

If you have any further questions on the use of Adizem-XL capsules ask your doctor or pharmacist.

4.

Possible side effects

Like all medicines, these capsules can cause side effects, although not everybody gets them.

Look out for the following severe allergic reactions. They have occurred in a small number of people,

although their exact frequency cannot be estimated:

swelling of the face or throat;

skin rash or itching especially those covering your whole body, severe flaking, blistering or peeling of

the skin, with or without a fever.

Tell your doctor immediately if you get any of these.

Very common side effects (May affect more than 1 in 10 people)

Swelling of the hands, ankles or feet.

Common side effects (May affect more than 1 in 100 people)

Feeling sick, abdominal pain, indigestion, constipation.

Dizziness, headache.

Flushing or redness of the skin, itching.

A fast, slow or irregular heartbeat.

Generally feeling unwell.

Tiredness.

Uncommon side effects (May affect up to 1 in 100 people)

Diarrhoea, being sick.

A feeling of faintness, especially on standing up.

Nervousness.

Difficulty in sleeping.

A worsening in liver function tests (seen in a blood test).

Rare side effects (May affect up to 1 in 1000 people)

Dry mouth.

Hives.

Frequency not known (Frequency cannot be estimated from the available data)

Heart failure which can cause shortness of breath or ankle swelling.

Inflammation of the liver.

Changes in muscle tone and/or abnormalities of movement.

Mood changes, including depression.

Skin problems such as increased sensitivity to sunlight.

A reduction in blood platelets which increases the risk of bleeding or bruising.

Breast enlargement in men.

Bleeding, tender or enlarged gums.

Inflammation of blood vessels (often with skin rash).

Sweating.

Low blood pressure.

You may see the remains of the capsules in your faeces. This should not affect how the capsules work.

Reporting of side effects

If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side effects

not listed in this leaflet. You can also report side effects directly via:

HPRA Pharmacovigilance

Kevin O’Malley House

Earlsfort Centre

Earlsfort Terrace

IRL – Dublin 2

Tel: +353 1 6764971

Fax: +353 1 6762517

Website: www.hpra.ie

e-mail: medsafety@hpra.ie

By reporting side effects you can help provide more information on the safety of this medicine.

5.

How to store Adizem-XL capsules

Keep out of the sight and reach of children.

Do not use any capsules after the expiry date which is stated on the carton. EXP 08 2020 means that

you should not take the capsules after the last day of that month i.e. August 2020.

Do not store your capsules above 25 °C.

Do not take your capsules if they are broken or crushed as this can be dangerous and can cause serious

problems such as overdose.

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw

away medicines you no longer use. These measures will help to protect the environment.

6.

Contents of the pack and other information

What Adizem-XL capsules contain

The active ingredient is diltiazem hydrochloride. Each capsule contains 120 mg, 180 mg, 240 mg or 300 mg

of diltiazem hydrochloride.

The other ingredients are:

Microcrystalline cellulose

Ethylcellulose

Colloidal anhydrous silica

Polysorbate

Dibutyl sebacate

Magnesium stearate

Sodium dodecyl sulphate

Gelatin

Shellac

Soya lecithin

2-ethoxyethanol

Dimeticone

Titanium dioxide (E171)

Iron oxide (E172)

The capsules also contain the following colourants:

120 mg, 180 mg and 240 mg – Erythrosine (E127) and indigo carmine (E132)

300 mg – Erythrosine (E127), indigo carmine (E132) and patent blue V (E131)

What Adizem-XL capsules look like and the contents of the pack

Adizem-XL capsules are marked DCR followed by the strength (e.g. 120, 180 etc) and are coloured as

follows: 120 mg - pale pink/navy blue, 180 mg - dark pink/royal blue, 240 mg - dark red/blue, 300 mg -

maroon/pale blue.

The capsules are packed in blister packs and then placed in boxes. In each box there are 28 capsules.

Marketing Authorisation Holder

Mundipharma Pharmaceuticals Ltd., Millbank House, Arkle Road, Sandyford, Dublin 18, Ireland.

Manufacturers

Mundipharma DC B.V., Leusderend 16, 3832 RC Leusden, Netherlands.

Bard Pharmaceuticals Limited, Cambridge Science Park, Milton Road, Cambridge, CB4 0GW, UK.

This leaflet is also available in large print, Braille or as an audio CD. To request a copy, please call

the RNIB Medicine Information Line on:

0044 1733 37 53 70

You will need to give details of the product name and reference number.

These are as follows:

Product name: Adizem-XL prolonged release capsules

Reference number: 1688/1/4

This leaflet was last revised in April 2019

ADIZEM

®

-XL capsules are protected by Irish Patent No. EP(IE) 0527637.

® ADIZEM, MUNDIPHARMA and the ‘mundipharma’ logo are Registered Trade Marks.

© 2010-2019 Napp Pharmaceuticals Limited.

Summary of Product Characteristics

1 NAME OF THE MEDICINAL PRODUCT

ADIZEM-XL 240 mg prolonged release capsules.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged release capsule contains 240 mg diltiazem hydrochloride.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Prolonged release capsules, hard.

Size 1 hard gelatin capsules approximately 19mm long with a dark red body and a blue cap, marked ‘DCR 240’.

4 CLINICAL PARTICULARS

4.1 Therapeutic Indications

Management of angina pectoris.

Treatment of mild to moderate hypertension.

ADIZEM-XL capsules are indicated for use in adults only.

4.2 Posology and method of administration

Posology

Adults:

The usual starting dose is one 240 mg capsule daily.

However, patients'

responses may vary and dosage requirements

can differ significantly between individual patients.

There is no evidence of any decrease in efficacy at higher doses.

If necessary the dose may be gradually increased to 300 mg or 360 mg per day.

Doses of 480 mg/day have been used

with benefit in some angina patients.

Elderly:

The usual starting dose is one 120 mg capsule daily.

If necessary the dose may be gradually increased but careful

monitoring of this group of patients is advised.

Paediatric population:

Not recommended for use in children.

Method of administration

Oral.

To be taken at 24 hour intervals.

The capsules should be swallowed whole and not chewed.

ADIZEM-XL should not be taken at the same time as an alcoholic beverage (see section 4.5).

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4.3 Contraindications

Sick sinus syndrome, second or third degree AV-block, severe bradycardia (less than 40 beats per minute). Congestive

heart failure and in patients with left ventricular failure with pulmonary congestion. Pregnant women or those of child

bearing potential. Concurrent use with dantrolene infusion is contraindicated because of the risk of ventricular

fibrillation (see section 4.5). Hypersensitivity to diltiazem or to any of the excipients.

4.4 Special warnings and precautions for use

Patients with bradycardia (risk of exacerbation), first degree AV block or a prolonged PR interval should be observed

closely. Diltiazem should be used with caution in patients with reduced left ventricular function.

Diltiazem is considered unsafe in patients with acute porphyria.

Isolated cases of moderate and transient increased liver transaminases have been observed at the start of treatment.

Isolated cases of clinical hepatitis have been reported, which resolved when diltiazem was withdrawn.

The use of diltiazem in diabetic patients may require adjustment of their control.

Prior to general anaesthesia, the anaesthesist must be informed of ongoing diltiazem treatment. Depression of cardiac

contractility, conductivity and automaticity, as well as the vascular dilatation associated with anaesthetics may be

potentiated by calcium channel blockers.

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.

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

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. Tablet residues from slow release formulations

of the product may pass into the patient’s stools; however, this finding has no clinical relevance.

4.5 Interaction with other medicinal products and other forms of interaction

Concomitant use contraindicated:

Dantrolene (infusion): Lethal ventricular fibrillation is regularly observed in animals when intravenous verapamil and

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

potentially dangerous (see section 4.3).

Concomitant use requiring caution:

Lithium: Risk of increase in lithium-induced neurotoxicity.

Nitrate derivatives: Increased hypotensive effects and faintness (additive vasodilatating effects): In all the patients

treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually

increasing doses.

Theophylline: Increase in circulating theophylline levels

Alpha-antagonists: Increased antihypertensive effects:

Concomitant treatment with alpha-antagonists may produce or aggravate hypotension. The combination of diltiazem

with an alpha-antagonist should be considered only with the strict monitoring of the blood pressure.

Amiodarone, digoxin: Increased risk of bradycardia:

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Caution is required when these are combined with diltiazem, particularly in elderly subjects and when high doses are

used.

Diltiazem hydrochloride may cause small increases in plasma levels of digoxin, requiring careful monitoring of

AV conduction.

Beta-blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus arrest), sino-atrial and atrio-

ventricular conduction disturbances and heart failure (synergistic effect). Patients with pre-existing conduction defects

should not receive the combination of diltiazem and beta-blockers.

Such a combination must only be used under close

clinical and ECG monitoring, particularly at the beginning of treatment.

Other antihypertensive drugs: Enhanced antihypertensive effect may occur with concomitant use of other

antihypertensive drugs (e.g. beta-blockers, diuretics, ACE-inhibitors) or drugs that cause hypotension such as

aldesleukin and antipsychotics.

Other antiarrhythmic agents:

Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not

recommended (additive risk of increased cardiac adverse effects). This combination should only be used under close

clinical and ECG monitoring.

Carbamazepine: Increase in circulating carbamazepine levels:

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

necessary.

Rifampicin: Risk of decrease of diltiazem plasma levels after initiating therapy with rifampicin: The patient should be

carefully monitored when initiating or discontinuing rifampicin treatment.

Anti-H

agents (cimetidine, ranitidine): Increase in plasma diltiazem concentrations. Patients currently receiving

diltiazem therapy should be carefully monitored when initiating or discontinuing therapy with anti-H

agents. An

adjustment in diltiazem daily dose may be necessary.

Protease inhibitors (e.g. atazanavir, ritonavir): Increase in plasma diltiazem concentrations.

Ciclosporin: Increase in circulating cyclosporin levels:

It is recommended that the cyclosporin dose be reduced, renal function be monitored, circulating cyclosporin levels be

assayed and that the dose should be adjusted during combined therapy and after its discontinuation.

General information to be taken into account:

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 metabolized by CYP3A4. A moderate (less than 2

fold) increase of diltiazem plasma concentration in

cases of co

administration with a stronger CYP3A4 inhibitor has been documented. Diltiazem is also a CYP3A4

isoform inhibitor. Co

administration with other CYP3A4 substrates may result in an increase in plasma concentration

of either co

administered drug (e.g. cilostazol, ivabradine, sirolimus, tacrolimus).

Care should be exercised in patients

taking these drugs. Concomitant use of diltiazem with cilostazol and ivabradine should be avoided.

administration of diltiazem with a CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.

Barbiturates (phenobarbital, primidone): serum levels of diltiazem may be decreased by concomitant usage of CYP3A4

inducers.

Phenytoin: serum levels of diltiazem may be decreased by concomitant usage of CYP3A4 inducers. Diltiazem may

increase serum levels of phenytoin.

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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.

Diltiazem hydrochloride may increase bioavailability of tricyclic antidepressants.

Corticosteroids (methylprednisolone): 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.

Statins (simvastatin, atorvastatin, lovastatin): 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.

ADIZEM-XL should not be taken at the same time as alcohol, as it may increase the release of diltiazem from the

prolonged release preparation.

In addition the combination of alcohol and diltiazem may have an additive vasodilatory

effect.

4.6 Fertility, pregnancy and lactation

Pregnancy

There is very limited data from the use of diltiazem in pregnant patients. Diltiazem has been shown to have

reproductive toxicity in certain animal species (rat, mice, rabbit - see section 5.3). Diltiazem is contraindicated during

pregnancy (see section 4.3), as well as in women of child

bearing potential not using effective contraception.

Breast feeding

Diltiazem is excreted in breast milk at low concentrations. Breast

feeding while taking this drug should be avoided. If

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

4.7 Effects on ability to drive and use machines

Diltiazem has been reported to cause adverse reactions such as dizziness (common) and malaise (common), which may

impair patients’ ability to drive or operate machinery to a varying extent depending on the dosage and individual

susceptibility. However, no studies have been performed. Therefore, patients should not drive or operate machinery if

affected.

4.8 Undesirable effects

The following frequencies are the basis for assessing undesirable effects:

Very common (

1/10);

Common (

1/100 to <1/10);

Uncommon (

1/1,000 to <1/100);

Rare (

1/10,000 to <1/1,000);

Very rare (<1/10,000);

Not known (cannot be estimated from the available data).

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Very

common

Common

Uncommon

Rare

Not known

Blood and

lymphatic system

disorders

Thrombocytopenia

Metabolism and

nutrition

disorders

Anorexia

Immune system

disorders

Hypersensitivity

Psychiatric

disorders

Nervousness,

insomnia

Mood changes

(including

depression)

Nervous system

disorders

Headache,

dizziness

Extrapyramidal

syndrome

Cardiac

disorders

Atrioventricular

block (may be of

first, second or

third degree;

bundle branch

block may occur),

palpitations

Bradycardia

Sinoatrial block,

congestive heart

failure

Vascular

disorders

Flushing

Orthostatic

hypotension

Vasculitis (including

leukocytoclastic vasculitis),

hypotension

Gastrointestinal

disorders

Constipation,

dyspepsia, gastric

pain, nausea

Vomiting, diarrhoea

mouth

Gingival hyperplasia,

Hepatobiliary

disorders

Hepatic enzymes

increase (AST, ALT,

LDH, ALP increase)

Hepatitis

Skin and

subcutaneous

tissue disorders

Erythema

Pruritus

Urticaria

Photosensitivity (including

lichenoid keratosis at sun

exposed skin areas),

angioneurotic oedema, rash,

erythema multiforme

(including Steven-Johnson's

syndrome and toxic

epidermal necrolysis),

hyperhidrosis, exfoliative

dermatitis, acute

generalized exanthematous

pustulosis, occasionally

desquamative erythema

with or without fever,

allergic dermatitis

Reproductive

system and breast

disorders

Gynecomastia

General

disorders and

administration

site conditions

Peripheral

oedema

Malaise,

fatigue

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Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation 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 via HPRA Pharmacovigilance, Earlsfort Terrace, IRL - Dublin 2; Tel: +353 1 6764971;

Fax: +353 1 6762517. Website: www.hpra.ie; E-mail: medsafety@hpra.ie.

4.9 Overdose

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

bradycardia with or without isorhythmic dissociation and atrioventricular conduction disturbances.

Treatment in a hospital setting with include gastric lavage and/or osmotic diuresis. Conduction disturbances may be

managed by temporary cardiac pacing.

Proposed corrective treatments: atropine, vasopressors, inotropic agents, glucagon and calcium gluconate infusion.

Symptomatic bradycardia and high grade atrioventricular block may respond to atropine and isoprenaline.

The formulation employs a prolonged release system which will continue to release diltiazem for some hours.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group:

Selective calcium channel blocker with direct cardiac effects

ATC Code: C08D B01

Diltiazem is a calcium antagonist.

It restricts the slow channel entry of calcium ions into the cell and so reduces the

liberation of calcium from stores in the sarcoplasmic reticulum.

This results in a reduction in the amount of available intra-cellular calcium and consequently a (1) reduction of

myocardial oxygen consumption, (2) dilation of small and large coronary arteries, (3) mild peripheral vasodilation, (4)

negative dromotropic effects, (5) reflex positive chronotropic and inotropic effects due to reflex sympathetic activity

are partially inhibited and result in a slight reduction or no change in heart rate.

The antihypertensive effect is due to the reduction in peripheral vascular resistance.

The antianginal effect is due to a reduction in the peripheral resistance, thereby decreasing the after-load, whilst a

reduction in the vasomotor tone of the coronary circulation maintains the coronary blood flow.

Cardiac contractility

and ventricular ejection fraction are unchanged.

Diltiazem increases exercise capacity and improves indices of

myocardial ischaemia in the angina patient.

Diltiazem relieves the spasm of vasospastic (Prinzmetal) angina.

5.2 Pharmacokinetic properties

Absorption

An oral dose of diltiazem is almost completely absorbed.

Despite this, diltiazem has a low bioavailability of

approximately 40% owing to hepatic first-pass metabolism.

Biotransformation

Diltiazem is extensively metabolised by the liver.

The desacetyl metabolite is considered to be approximately 25% to

50% as potent a coronary vasodilator as diltiazem and is present in plasma at concentrations of 10% to 20% of parent.

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Elimination

The mean elimination half life of diltiazem is around 4 hours, but this is extended from prolonged-release

formulations.

Mean plasma concentrations in elderly subjects and patients with renal and hepatic insufficiency are

higher than in young subjects.

Linearity/non-linearity

This process of first-pass metabolism process is saturable at higher doses of the drug.

This results in a non-linear

accumulation and higher blood concentrations at steady state than would be anticipated from those following a single

dose.

From modified-release preparations, the prolonged delivery of diltiazem can significantly reduce the degree of

non-linearity associated with conventional formulations.

5.3 Preclinical safety data

Genotoxicity and Carcinogenicity

Diltiazem was not genotoxic when tested in vitro in two bacterial mutation tests with and without metabolic activation,

and in two clastogenicity assays.

Diltiazem was not carcinogenic in two long term carcinogenicity studies, in rats and mice.

Reproductive and developmental toxicity

Diltiazem was toxic to the developing embryo in studies in mice, rats and rabbits when dosed to the mother at critical

stages during organ development.

Skeletal malformations ocurred in the limbs, tail and ribs of all three species.

Diltiazem had an adverse effect upon male fertility in rats, with decreases in sperm count, sperm motility and

epididymal weight, although these effects were reversible on cessation of dosing.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose

Ethylcellulose N10

Colloidal anhydrous silica

Polysorbate 80

Dibutyl sebacate

Magnesium stearate

Capsule shell

Erythrosine (E127)

Iron oxide red and yellow (E172)

Indigo carmine (E132)

Titanium dioxide (E171)

Gelatin

Sodium laurilsulfate

Printing Ink

Shellac

Propylene glycol

Simeticone

Titanium dioxide (E171)

6.2 Incompatibilities

Not applicable.

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6.3 Shelf life

2 years.

6.4 Special precautions for storage

Do not store above 25°C.

6.5 Nature and contents of container

PVdC coated PVC blister packs with aluminium foil backing (4, 28 and 30 capsules).

Not all pack sizes may be marketed

6.6 Special precautions for disposal of a used medicinal product or waste materials derived from

such medicinal product and other handling of the product

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Mundipharma Pharmaceuticals Limited

Millbank House

Arkle Road

Sandyford

Dublin 18

Ireland

8 MARKETING AUTHORISATION NUMBER

PA1688/001/006

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

Date of first authorisation:

16/12/1994

Date of last renewal:

16/12/2009

10 DATE OF REVISION OF THE TEXT

March 2017

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