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DILTIAZEM MODIFIED RELEASE TABLETS 60MG
Active substance(s): DILTIAZEM HYDROCHLORIDE
NAME OF THE MEDICINAL PRODUCT
Diltiazem modified release tablets 60mg.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains diltiazem hydrochloride 60mg.
For full list of excipients, see section 6.1.
White flat modified release tablets with C/066 on one side and the company logo on
Prophylaxis and treatment of angina pectoris.
Posology and method of administration
Adults: The usual maintenance dose is one tablet (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.
Paediatric population: Not recommended.
Method of Administration
For oral administration. Tablets should be swallowed whole with a little water.
Hypersensitivity to diltiazem or to any of the excipients listed in section 6.1
Acute cardiac infarct with complications (bradycardia, severe hypotension,
left heart insufficiency)
Bradycardia (pulse rate, at rest, of less than 50 bpm), hypotension (less than
90mm Hg systole), Second or third degree AV block or sick sinus syndrome
except in the presence of a functioning ventricular pacemaker
Severe bradycardia (below 40 bpm)
Atrial fibrillation/flutter and simultaneous presence of a WPW (WolffParkinson-White) syndrome (increased risk of triggering a ventricular
Manifest myocardial insufficiency
Concomitant use of dantrolene infusion due to the risk of ventricular
fibrillation (see section 4.5)
Pregnant women, women of child bearing potential and lactation (see section
Combination with ivabradine (see section 4.5).
Special warnings and precautions for use
The use of diltiazem hydrochloride in diabetic patients may require adjustment
of their control.
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 (see section 4.3) detected on the electrocardiogram. Diltiazem prolongs AV
node refractory periods without significantly prolonging sinus node recovery time,
except in patients with sick sinus syndrome. This effect may rarely result in
abnormally slow heart rates (particularly in patients with sick sinus syndrome)
or second or third degree AV block (see section 4.5).
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.
The product should be used with caution in patients with hepatic dysfunction.
Abnormalities of liver function may occur during therapy. Very occasional
reports of abnormal liver function have been received; these reactions have
been reversible upon discontinuation of therapy.
Prior to general anaesthesia, the anaesthetist must be informed of ongoing diltiazem
treatment (see section 4.5). Depression of cardiac contractility, conductivity and
automaticity as well as the vascular dilatation associated with anaesthetics may be
potentiated by calcium channel blockers.
Diltiazem is not recommended for use in patients with acute porphyria unless
other safer alternatives are not available.
There have been reports of calcium-channel blockers exacerbating muscle
weakness in patients with myasthenia gravis. Diltiazem should be used with
caution in such patients.
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
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
Diltiazem does not affect the glucose or endogenous insulin responses to
As with any drug given over prolonged periods, laboratory parameters should be
monitored at regular intervals.
Patients with rare hereditary problems of galactose intolerance, the LAPP lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
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 with ivabradine is contraindicated due to the additional heart
rate lowering effect of diltiazem to ivabradine (see section 4.3).
Concomitant use requiring caution:
Anaesthetists should be warned that a patient is taking diltiazem. The
cardiac contractility, conductivity, and automaticity as well as the vascular
associated with anaesthetics may be potentiated by calcium channel blockers.
used concomitantly, anaesthetics and calcium channel blockers should be
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
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. Amiodarone in combination with diltiazem may
also cause AV block and myocardial depression.
It is recommended that the plasma digoxin concentrations be assayed and that
the dose should be adjusted if necessary. Cardiac glycosides may cause a
greater degree of AV blocking, reduce the heart rate or induce a hypotensive
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. Co- administration with other CYP3A4 substrates may result in an
increase in plasma concentration of either co-administered drug. Coadministration of diltiazem with a CYP3A4 inducer may result in a decrease
of diltiazem plasma concentrations.
Diltiazem hydrochloride should only be administered with great care to
receiving concurrent treatment with antihypertensives or other hypotensive
agents including halogenated anaesthetics or drugs with moderate protein
Diltiazem hydrochloride will not protect against effects of withdrawal of
ßadrenoceptor blocking agents, nor the rebound effects seen with various
There may be an additive effect when diltiazem is used with drugs which may
induce bradycardia or with other antihypertensives.
Diltiazem increases plasma levels of imipramine and possibly other tricyclic
anti-depressants, 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 halflife. Special care should be taken when prescribing short-acting
benzodiazepines metabolised by the CYP3A4 pathway in patients using
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 CYP3A4metabolised 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.
Fertility, 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 (see section 4.3).
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
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.
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
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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 the Yellow Card Scheme at:
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.
Experience of over dosage in man is limited but cases of spontaneous recovery
have been reported. However, it is recommended that patients with suspected
overdose should be placed under observation in a coronary care unit with
facilities available for treatment of any possible hypotension and conduction
disturbances that may occur. Conduction disturbances may be managed by
temporary cardiac pacing. Most patients suffering from over dosage of
diltiazem become hypotensive within 8 hours of ingestion. With bradycardia
and first to third degree atrioventricular block also developing cardiac arrest
may ensue. Hyperglycaemia is also a recognised complication. The
elimination half-life of diltiazem after overdosage is estimated to be about 5.5
- 10.2 hours. If a patient presents early after overdose, gastric lavage should be
performed under hospital supervision and activated charcoal administered to
reduce diltiazem absorption.
Hypotension should be corrected with plasma expanders, intravenous calcium
gluconate and inotropic agents (dopamine, dobutamine or isoprenaline).
Symptomatic bradycardia and high grade AV block may respond to atropine,
isoprenaline or occasionally cardiac pacing which may be useful if cardiac
Proposed corrective treatments: atropine, vasopressors, inotropic agents,
glucagon and calcium gluconate infusion.
Pharmacotherapeutic group: Selective Calcium Channel Blockers ATC Code:
Mechanism of action
Diltiazem is a calcium channel antagonist which restricts the entry of calcium
ions into the cell through the slow voltage dependent channels and reduces the
liberation of calcium from the endoplasmic reticulum. This results in a
reduced amount of available intracellular calcium. The haemodynamic actions
of diltiazem are:
- Peripheral and coronary vasodilatation.
- Decrease in myocardial oxygen consumption.
- Reduction of blood pressure particularly in hypertension.
- Increase in renal blood flow and urinary sodium excretion.
Diltiazem has pharmacologic actions similar to those of other calcium channel
blocking agents such as nifedipine or verapamil. The principal physiologic
action of diltiazem is to inhibit the transmembrane influx of extracellular
calcium ions across the membranes of myocardial cells and vascular smooth
Calcium plays important roles in the excitation-contraction coupling processes
of the heart and vascular smooth muscle cells and in the electrical discharge of
the specialised conduction cells of the heart. The membranes of these cells
contain numerous channels that carry a slow inward current and that are
selective for calcium.
By inhibiting calcium influx, diltiazem inhibits the contractile processes of
cardiac and vascular smooth muscle, thereby dilating the main coronary and
systemic arteries. Dilation of systemic arteries by diltiazem results in a
decrease in total peripheral resistance, a decrease in systemic blood pressure
and a decrease in the afterload of the heart. The reduction in afterload, seen at
rest and with exercise, and its resultant decrease in myocardial oxygen
consumption are thought to be responsible for the beneficial effects of
diltiazem in patients with chronic stable angina pectoris. In patients with
prinzmetal variant angina, inhibition of spontaneous and ergonovine-induced
coronary artery spasm by diltiazem results in increased myocardial oxygen
a) General Characteristics
When taken orally diltiazem is almost completely absorbed. Despite this, the
absolute bioavailability is 40% due to extensive first pass metabolism.
Bioavailability is not affected by age. Diltiazem is 78-87% bound to plasma
proteins but only 35-40% to albumin. The peak plasma concentration is
reached in about three hours after single dose of diltiazem 90 mg CR tablets.
The Cmax value was 50-65 ng/ml. Capsules seem to have a similar
bioavailability to tablets (30-40%), with peak concentrations for the prolonged
release product after 8-11 hours compared with 1-2 hours after the
conventional release product. The relatively low bioavailability is due to first
pass metabolism in the liver to an active metabolite.
Diltiazem hydrochloride is lipophilic and has a high volume of distribution.
Typical study results are in the range of 3-8 litres/kg. Protein binding is about
80% and is not concentration-dependent at levels likely to be found clinically.
Protein binding does not appear to be influenced by phenylbutazone, warfarin,
propranolol, salicylic acid or digoxin.
Diltiazem hydrochloride is extensively metabolised in the liver by
deacetylation and N-demethylation followed by O-demethylation or
deacetylation. N-monodesmethyl diltiazem is the predominant metabolite
followed quantitatively by the desacetyl metabolite, which has some
hypotensive potency. The efficacy of the metabolites, desacetyl diltiazem and
N-monodesmethyl diltiazem is 25-50% and about 20% respectively of that of
diltiazem. In liver function disorders delayed metabolism in the liver is likely.
These metabolites are converted to conjugates, generally the glucuronide or
Diltiazem is excreted in the form of its metabolites (about 35%) and in the
non-metabolised form (about 2-4%) via the kidneys while about 60% is
excreted via the faeces Diltiazem is mainly excreted as metabolites in the urine
and faeces and only 1-3% of the dose is excreted as the parent compound in
urine. The average elimination half life period for diltiazem is 6-8 hours but
may vary between 2 and 11 hours. Although the elimination half life is not
changed after repeated oral administration, diltiazem and also the desacetyl
metabolite show a slight accumulation in the plasma.
b) Characteristics in Patients
Decreased first-pass metabolism in the elderly tends to result in increased
concentrations of calcium antagonists but no major changes have been found
with diltiazem. Renal impairment did not cause significant changes in
diltiazem pharmacokinetics. Plasma concentrations of diltiazem also tend to be
higher in hepatic cirrhosis due to impaired oxidative metabolism.
Preclinical safety data
Chronic toxicity studies in rats revealed no remarkable changes at oral doses
up to 125 mg/kg/day although there was 60% mortality at this dose. In dogs
chronically treated with oral doses of 20 mg/kg/day, transient rises in SGPT
Embryotoxicity has been reported in mice, rats and rabbits following
i.p.administration of diltiazem. Main types of malformations included limb
and tail defects with a small number of vertebral and rib deformities also
List of excipients
Lactose, hydrogenated castor oil, macrogol 6000 and magnesium stearate.
Special precautions for storage
Protect from light.
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.
Instruction for use, handling and disposal
The tablets should not be crushed or chewed, but swallowed whole with a
glass of water.
MARKETING AUTHORISATION HOLDER
Crescent Pharma Limited
Units 3 and 4
Quidhampton Business Units
Hants RG25 3ED
MARKETING AUTHORISATION NUMBER
DATE OF FIRST AUTHORISATION/RENEWAL OF
28 May 2004
DATE OF REVISION OF THE TEXT