Dilzem SR

Dilzem SR 120mg Prolonged-release Hard Capsules

Each Dilzem SR 120mg capsule contains diltiazem hydrochloride 120mg.

Excipient with known effect

Sucrose 25.2mg in each SR 120mg capsule.

Prolonged-release capsule, hard.

Buff coloured, hard gelatin capsules, printed with 120mg and containing roughly spherical white to off-white beads.

Treatment of angina pectoris including Prinzmetal's angina.

Treatment of mild to moderate hypertension.

Posology

Adults

Hypertension: The usual initial dose is 90 mg twice daily (corresponding to 180 mg of diltiazem hydrochloride). Depending upon clinical response the patient's dosage may be increased to 180 mg twice daily if required.

Angina Pectoris: The usual initial dose is 90 mg twice daily (corresponding to 180 mg of diltiazem hydrochloride). Depending upon clinical response the patient's dosage may be increased to 180 mg twice daily if required.

Elderly patients and those with renal or hepatic impairment

Dosage should commence at the lower level of 60 mg twice daily and be increased slowly. Do not increase the dose if the heart rate falls below 50 beats per minute.

Paediatric population

Children

This product is not recommended for use in children.

Method of administration

Oral use only.

- Use during pregnancy, in women of child-bearing potential and lactation

- Concomitant administration of dantrolene infusion due to the risk of ventricular fibrillation.

- Shock

- Acute cardiac infarct with complications (bradycardia, severe hypotension, left heart insufficiency)

- Bradycardia (pulse rate, at rest, of less than 50 bpm), hypotension (less than 90 mm Hg systole), second or third degree AV block or sick sinus syndrome, except in the presence of a functioning ventricular pacemaker

- Severe bradycardia (less than 40 beats per minute)

- Atrial fibrillation/flutter and simultaneous presence of a WPW (Wolff-Parkinson-White) syndrome (increased risk of triggering a ventricular tachycardia)

- Manifest myocardial insufficiency

- Left ventricular failure with pulmonary congestion

- Combination with ivabradine

- Capsules should not be sucked or chewed.

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

- Plasma diltiazem concentrations can be increased in the elderly and 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. The 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.

- 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.

- First degree AV block or prolonged PR interval. 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.

- Close observation is necessary in patients with reduced left ventricular function and bradycardia (risk of exacerbation) or with a 1st degree AV block detected on the electrocardiogram (risk of exacerbation and rarely of complete block) or prolonged PR interval.

- 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

- 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.

- Diltiazem does not affect the glucose or endogenous insulin responses to hypoglycaemia.

- Owing to the presence of sucrose, patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

As with any drug given over prolonged periods, laboratory parameters should be monitored at regular intervals.

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.

Tabulated list of adverse reactions

The frequencies of adverse reactions are ranked according to the following: 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.

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: www.mhra.gov.uk/yellowcard.

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 overdosage 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 overdosage 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 standstill occurs.

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

Pharmacotherapeutic group: Calcium channel Blocker, ATC code: C08D B01

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 muscle cells.

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 delivery.

a) General Characteristics

Absorption

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 C_max 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.

Distribution

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.

Metabolism

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 the sulphate.

Elimination

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 plasma 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.

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 were observed. 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 noted.

Fumaric acid

Talc

Povidone

Sugar spheres (containing sucrose and maize starch)

Ammonio methacrylate copolymer Type B

Ammonio methacrylate copolymer Type A

The capsule shell contains:

Yellow iron oxide (E172)

Erythrosine (E127)

Titanium dioxide (E171)

Gelatin

The printing ink contains:

Shellac

Black iron oxide (E172)

Propylene glycol (E1520)

Not applicable.

Three years from date of manufacture for all presentations.

Do not store above 25°C. Store in the original package in order to protect from light and moisture.

Opaque PVC/PVDC blister pack containing 56, 60 or 100 capsules.

Not all pack sizes may be marketed.

Not applicable.

Cephalon UK Limited

Ridings Point

Whistler Drive

Castleford

West Yorkshire

WF10 5HX

United Kingdom

Dilzem SR 120 mg - PL 16260/0019

14 April 2011

04/01/2016