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DILTIAZEM MODIFIED RELEASE TABLETS 60MG

Active substance(s): DILTIAZEM HYDROCHLORIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Diltiazem modified release tablets 60mg.

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains diltiazem hydrochloride 60mg.

3

PHARMACEUTICAL FORM
White flat modified release tablets with C/066 on one side and the company logo on
the other.

4.

CLINICAL PARTICULARS

4.1.

Therapeutic indications
Prophylaxis and treatment of angina pectoris.

4.2.

Posology and method of administration
Adults: 60mg three times daily.
As patient responses may vary the dose can be increased to a maximum of
360mg daily in divided doses.
Higher doses up to 480mg/day have been used with benefit in some patients
especially in unstable angina. There is no evidence of any decrease in efficacy
at high doses. Diltiazem has not been reported to precipitate angina.
Elderly patients and patients with impaired hepatic or renal function: initially
60mg twice daily, monitoring of the heart rate should be carried out. Do not
increase the dose if the rate falls below 50 beats per minute.
Children: Not recommended.
Route of Administration - Oral.

4.3

Contra-indications








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
Severe bradycardia (below 40 bpm)
Left ventricular failure with pulmonary congestion
Hypersensitivity to diltiazem or to any of the excipients.
Concomitant use of dantrolene infusion (see section 4.5)
Pregnant women or those of child bearing potential, lactation

Additionally, for the intravenous forms, patients known to have an accessory bypass
(Wolf-Parkinson-White syndrome or short PR syndrome), and who develop atrial
fibrillation or flutter, should not be administered intravenous diltiazem.

4.4

Special warnings and precautions for use
Close observation is necessary in patients with reduced left ventricular function,
bradycardia (risk of exacerbation) or with a first degree AV block or prolonged PR
interval detected on the electrocardiogram (risk of exacerbation and rarely, of
complete block).
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.
Prior to general anaesthesia, the anaesthetist 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.
Calcium channel blocking agents, such as diltiazem may be associated with mood
changes, including depression. Early recognition of relevant symptoms is important,
especially in predisposed patients. In such cases, drug discontinuation should be
considered.
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 galactose intolerance, the LAPP lactase
deficiency or glucose-galactose malabsorption should not take this medicine.

4.5

Interaction with other medicinal products and other forms of interactions

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 anti-hypertensive 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 may cause small increases in the plasma levels of digitalis.
Beta-blockers: Possibility of rhythm disturbances (pronounced bradycardia, sinus
arrest), sino-atrial and atrio-ventricular conduction disturbances and heart failure
(synergistic effect). Such a combination must only be used under close clinical and
ECG monitoring, particularly at the beginning of treatment.
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.
Ciclosporin: Increase in circulating ciclosporin levels. It is recommended that the
ciclosporin dose be reduced, renal function be monitored, circulating ciclosporin
levels be assayed and that the dose should be adjusted during combined therapy and
after its discontinuation.

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. Coadministration with other CYP3A4 substrates may result in an increase in plasma
concentration of either co-administered drug. Co-administration of diltiazem with a
CYP3A4 inducer may result in a decrease of diltiazem plasma concentrations.
Diltiazem increases plasma levels of imipramine and possibly other tricyclic antidepressants, tacrolimus, sirolimus and cilostazol.
Diltiazem increases plasma levels of phenytoin; phenytoin and phenobarbital reduce
the effects of diltiazem.
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 metabolised by the
CYP3A4 pathway in patients using diltiazem.
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: 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 (e.g atorvastatin, fluvastatin, and simvastatin) may be
increased with concomitant use of diltiazem. An adjustment of the dose of statin may
be necessary (see also product information of the relevant statin). When possible, a
non CYP3A4-metabolised statin (e.g pravastatin) should be used together with
diltiazem, otherwise close monitoring for signs and symptoms of a potential statin
toxicity is required.
Ritonavir and amprenavir may increase the plasma levels of diltiazem.
Diltiazem may increase the hypotensive effects of ACE inhibitors, angiotensin-II
antagonists, aldesleukin, alprostadil, MAOIs, antipsychotics and moxisylate and
diuretics.
Possible increase in the risk of bradycardia with mefloquine.
Clearance of nifedipine is reduced by diltiazem.

4.6

Use during pregnancy and lactation

The use of diltiazem in pregnancy or in women of child bearing potential is
contraindicated. 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 therefore not recommended during pregnancy,
as well as in women of child-bearing potential not using effective contraception.
Diltiazem hydrochloride 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
On the basis of reported adverse drug reactions, i.e. dizziness (common), malaise
(common), the ability to drive and use machines could be altered. However, no
studies have been performed.

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).
Within each frequency grouping, adverse events are presented in order of decreasing
seriousness.

Very
common

Common

Uncommon

Blood and
lymphatic
system
disorders

Rare

Not known
Thrombocytopenia

Psychiatric
disorders

Nervousness,
insomnia

Mood changes (including
depression)

Nervous system
disorders

Headache,
dizziness.

Extrapyrimidal 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
hypotension

Vascular
disorders

Flushing

Orthostatic
hypotension

Vasculitis (including
leukocytoclastic
vasculitis)

Gastrointestinal
disorders

Constipation,
dyspepsia, gastric
pain, nausea

Hepatobiliary
disorders

Vomiting,
diarrhoea

Dry
mouth

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

Skin and
subcutaneous
tissue disorders

Erythema

Hepatitis

Urticaria

Reproductive
system and
breast disorders
General
disorders and
administration
site conditions

4.9

Gingival hyperplasia

Photosensitivity
(including lichenoid
keratosis at sun-exposed
skin areas), angioneurotic
oedema, rash, erythema
multiforme (including
Steven-Johnson’s
syndrome and toxic
epidermal necrolysis),
sweating, exfoliative
dermatitis, acute
generalised
exanthematous
pustulosis, occasionally
desquamative erythema
with or without fever
gynaecomastia.

Peripheral
oedema

Malaise, asthenia,
fatigue.

Overdose symptoms, emergency procedures, antidotes
The clinical effects of acute overdose can involve pronounced hypotension possibly
leading to collapse, sinus bradycardia with or without isorhythmic dissociation, and
atrioventricular conduction disturbances.
Should overdose occur, observation in a coronary care unit is advised. It is reported
that spontaneous recovery usually occurs. Treatment, in a hospital setting, will
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.

5.

PHARMACOLOGICAL PROPERTIES

5.1.

Pharmacodynamic properties

Pharmacotherapeutic group: Selective Calcium Channel Blockers with Direct
Cardiac Effects, Benzothiazepine derivatives.
ATC Code: C08D B01
Diltiazem is a calcium channel blocker interfering with the inward
displacement of calcium ions through the slow channels of cell membranes.
The site of action is particularly the myocardial cells and the cells of vascular
smooth muscle.

5.2.

Pharmacokinetic properties
There is sparse information reported on the pharmacokinetics of diltiazem but
due to the first pass hepatic uptake effect bioavailability is variable and about
50%. Literature reports suggest that diltiazem has a mean half life of 4-6
hours. Extensive hepatic metabolism occurs and little unchanged drug is
excreted in the urine. The drug is 80-85% protein bound.

5.3.

Preclinical safety data
There are no pre-clinical data of relevance to the prescriber that are additional
to that already included in other sections of the SPC.

6.

PHARMACEUTICAL PARTICULARS

6.1.

List of excipients
Lactose, hydrogenated castor oil, macrogol 6000 and magnesium stearate.

6.2.

Incompatibilities
None known.

6.3.

Shelf life
36 months.

6.4.

Special precautions for storage
Protect from light.

6.5.

Nature and contents of container
Securitainers, sealed with low density polythene snap-on closure in pack sizes
28, 30, 50, 56, 60, 84, 90, 100, 112 and 250. Alternatively, heat sealed PVC /
PVdC / aluminium blister packs 250 micrometres PVC coated (inside) with
40gsm PVdC. Nominal 20 micrometres aluminium. Strips of 10 packed into
cartons of 30, 60, 90, 100, and 1,000; strips of 14 packed into cartons of 28,
56, 84 and 112.

6.6.

Instruction for use, handling and disposal
The tablets should not be crushed or chewed, but swallowed whole with a
glass of water.

7.

MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Units 3 and 4
Quidhampton Business Units
Polhampton Lane
Overton
Hants RG25 3ED

8.

MARKETING AUTHORISATION NUMBER
PL 20416/0066

9.
DATE OF FIRST AUTHORISATION/RENEWAL OF
AUTHORISATION
28 May 2004

10

DATE OF REVISION OF THE TEXT
03/06/2016

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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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