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ADIZEM-SR TABLETS 120MG

Active substance(s): DILTIAZEM HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
ADIZEM-SR tablets 120 mg

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
Diltiazem Hydrochloride 120 mg

Excipients: also contains 120 mg lactose and 0.8 mg sucrose per tablet.
For a full list of excipients see section 6.1.

3.

PHARMACEUTICAL FORM
White film-coated capsule–shaped, prolonged release tablets. The tablets are
marked 120/DL on one side and with a scoreline on the other.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic Indications
For the management of angina pectoris. For the treatment of mild to moderate
hypertension.

4.2.

Posology and Method of Administration
Route of administration
Oral.
Dosage may be taken with or without food, and should be swallowed whole
and not chewed.
Angina
Adults:
The usual initial dose is 90 mg twice-daily. Dosage may be increased
gradually to 120 mg twice-daily, or 180 mg twice- daily if required. Patients'

responses may vary and dosage requirements can differ significantly between
individual patients.
Elderly and patients with impaired renal or hepatic function:
In the elderly, dosage should commence at 60 mg diltiazem hydrochloride
twice daily and the dose carefully titrated as required.
Hypertension
Adults:
The usual dose is one ADIZEM-SR 120 mg tablet or capsule twice daily.
Patients may benefit by titrating from a lower total daily dose.
Elderly and patients with impaired renal or hepatic function:
The starting dose should be 60 mg diltiazem hydrochloride twice daily,
increasing to one ADIZEM-SR 90 mg capsule twice-daily and then to one
ADIZEM-SR 120 mg tablet or capsule twice-daily if clinically indicated.
Children:
The ADIZEM preparations are not recommended for children. Safety and
efficacy in children has not been established.
In order to avoid confusion, it is suggested that patients, once titrated to an
effective dose using either ADIZEM tablets or capsules, should remain on this
treatment and should not be changed between different presentations.

4.3

Contraindications
Pregnancy and in women of child-bearing capacity. Patients with severe bradycardia
(less than 40 bpm), second or third degree heart block, sick sinus syndrome,
decompensated cardiac failure, patients with left ventricular failure with pulmonary
congestion. Concurrent use with dantrolene infusion 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
The product should be used with caution in patients with reduced left ventricular
function. Patients with bradycardia (risk of exacerbation), first degree AV block or
prolonged PR interval should be observed closely.
Diltiazem is considered unsafe in patients with acute porphyria.

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.
Patients with rare hereditary problems of fructose intolerance, glucose-galactose
malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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:
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, ACEinhibitors) 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-H2 agents (cimetidine, ranitidine): Increase in plasma diltiazem concentrations.
Patients currently receiving diltiazem therapy should be carefully monitored when
initiating or discontinuing therapy with anti-H2 agents. An adjustment in diltiazem
daily dose may be necessary.
Protease inhibitors (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.
Co-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.
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 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.
The combination of alcohol and diltiazem may have an additive vasodilatory effect.

4.6

Pregnancy and lactation
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). Diltiazem is contraindicated during pregnancy (see section 4.3), as well as in
women of child-bearing potential not using effective contraception.
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 CIOMS frequency rating is used, when applicable: 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).
Very
common

Common

Blood and
lymphatic
system
disorders
Psychiatric
disorders
Nervous system
disorders
Cardiac
disorders

Vascular
disorders
Gastrointestinal
disorders

Rare

Not known
Thrombocytopenia

Nervousness,
insomnia

Mood changes
(including
depression)
Extrapyramidal
syndrome
Sinoatrial block,
congestive heart
failure

Headache,
dizziness
Atrioventricular Bradycardia
block (may be
of first, second
or third degree;
bundle branch
block may
occur),
palpitations
Flushing
Orthostatic
hypotension
Constipation,
dyspepsia,
gastric pain,
nausea

Hepatobiliary
disorders

Skin and
subcutaneous
tissue disorders

Uncommon

Vomiting,
diarrhoea

Hepatic
enzymes
increase
(AST, ALT,
LDH, ALP
increase)
Erythema

Dry
mouth

Vasculitis (including
leukocytoclastic
vasculitis), hypotension
Gingival hyperplasia,
gastrointestinal disorder

Hepatitis

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

Very
common
Reproductive
system and
breast
disorders
General
disorders and
administration
site conditions

4.9.

Common

Uncommon

Rare

Not known
Gynecomastia

Peripheral Malaise, fatigue
oedema

Overdose
The clinical symptoms of acute intoxication may include pronounced
hypotension or even collapse and sinus bradycardia with or without
atrioventricular conduction defects.
The patient should be closely monitored in hospital to exclude arrhythmias or
atrioventricular conduction defects. Gastric lavage and osmotic diuresis should
be undertaken when considered appropriate. Symptomatic bradycardia and
high grade atrioventricular block may respond to atropine, isoprenaline or
occasionally temporary cardiac pacing.
Hypotension may require correction with plasma volume expanders,
intravenous calcium gluconate and positive inotropic agents. The formulation
employs a prolonged release system which will continue to release diltiazem
for some hours.

5.

PHARMACOLOGICAL PROPERTIES
Pharmacotherapeutic group: Selective calcium channel blocker with direct
cardiac effects
ATC Code: C08D B01

5.1

Pharmacodynamic Properties
Diltiazem is a calcium antagonist which restricts the slow channel entry of
calcium ions into the cell and so reduces the liberation of calcium from stores
in the endoplasmic reticulum. This results in a reduction in the amount of
available intra-cellular calcium and consequently:
1)
2)
3)
4)

Reduction of myocardial oxygen consumption.
Dilation of small and large coronary arteries.
Mild peripheral vasodilation.
A negative dromotropic effect.

5)

The reflex positive chronotropic and inotropic effects due to reflex
sympathetic activity are partially inhibited. This results in a slight
reduction or no change in heart rate.

The antianginal effect is due to a reduction in cardiac oxygen demand with
maintenance of coronary blood flow. Cardiac contractility and ventricular
ejection fraction are unchanged. Treatment with diltiazem increases exercise
capacity, improves the indices of myocardial ischaemia in the angina patient
and relieves the spasm of vasospastic (Prinzmetal's) angina.

5.2

Pharmacokinetic Properties
An oral dose of diltiazem is almost completely absorbed. Despite this,
Diltiazem has a low bioavailability owing to hepatic first pass metabolism.
Diltiazem is metabolised extensively and only 1.0 to 3.0% of the dose is
excreted in the urine as unchanged diltiazem. The release of the drug has been
prolonged in the 120 mg tablet by special pharmaceutical technology. The
high peak concentrations of the absorption phase have been eliminated. This
allows the tablet to be administered twice-daily.

5.3

Pre-clinical Safety Data
There are no pre-clinical data of relevance to the prescriber which are
additional to that already included in other sections of the SPC.

6.

PHARMACEUTICAL PARTICULARS

6.1

List of Excipients
Lactose
Hydrogenated castor oil
Colloidal aluminium hydroxide
Acrylic resin
Talc
Magnesium stearate
Hypromellose
Sucrose
Glycerol 85%
Titanium dioxide (E171)
Polysorbate 80

6.2

Incompatibilities
None known.

6.3

Shelf Life
36 months.

6.4

Special precautions for storage

Do not store above 25°C.
Store in the original package.
6.5
Nature and Contents of Container
Aluminium foil backed PVdC/PVC blister packs containing 8, 28 or 56
tablets.
Amber glass bottles with a pilfer-proof closure containing 56 tablets.
Polypropylene containers with polyethylene lids containing 28 or 56 tablets.

6.6

Instructions for Use/Handling
None.

ADMINISTRATIVE DATA
7.

MARKETING AUTHORISATION HOLDER

Napp Pharmaceuticals Ltd
Cambridge Science Park
Milton Road
Cambridge
CB4 0GW

8.

MARKETING AUTHORISATION NUMBER
PL 16950/0009

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
21st December 1989 / 23rd September 2003

10

DATE OF REVISION OF THE TEXT
10/12/2010

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Source: Medicines and Healthcare Products Regulatory Agency

Disclaimer: Every effort has been made to ensure that the information provided here is accurate, up-to-date and complete, but no guarantee is made to that effect. Drug information contained herein may be time sensitive. This information has been compiled for use by healthcare practitioners and consumers in the United States. The absence of a warning for a given drug or combination thereof in no way should be construed to indicate that the drug or combination is safe, effective or appropriate for any given patient. If you have questions about the substances you are taking, check with your doctor, nurse or pharmacist.

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