Dilzem XL 120mg Prolonged-release Hard Capsules

Dilzem XL 180mg Prolonged-release Hard Capsules

Dilzem XL 240mg Prolonged-release Hard Capsules

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

Each Dilzem XL 180mg capsule contains diltiazem hydrochloride 180mg.

Each Dilzem XL 240mg capsule contains diltiazem hydrochloride 240mg.

Excipients: Sucrose 25.2mg in each XL 120mg capsule.

Sucrose 37.8mg in each XL 180mg capsule.

Sucrose 50.4mg in each XL 240mg capsule.

For full list of excipients, see Section 6.1.

Prolonged-release capsule, hard.

White, hard gelatin capsules, printed with e120 and containing roughly spherical white to off-white beads.

White, hard gelatin capsules, printed with e180 and containing roughly spherical white to off-white beads.

White, hard gelatin capsules, printed with e240 and containing roughly spherical white to off-white beads.

Prophylaxis and treatment of angina pectoris.

Treatment of mild to moderate hypertension.

Oral use only.

Adults:

Hypertension: The usual initial dose is one 180mg capsule per day (corresponding to 180mg of diltiazem hydrochloride once daily). Depending upon the clinical response the dosage may be increased stepwise to 360mg/day if required.

Angina Pectoris: The usual initial dose is one 180mg capsule per day (corresponding to 180mg of diltiazem hydrochloride once daily). Depending upon the clinical response the dosage may be increased stepwise to 360mg/day if required.

Elderly patients and those with renal or hepatic impairment:

Dosage should commence at the lower level of 120mg once daily and be increased slowly. Do not increase the dose if the heart rate falls below 50 beats per minute.

Children:

This product is not recommended for use in children.

- Use in women of child-bearing potential

- 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 heart block or sick sinus syndrome, except in the presence of a functioning ventricular pacemaker

- 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 stasis

- Hypersensitivity to diltiazem or any of the excipients

- Capsules should not be sucked or chewed.

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

- 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. Diltelan 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 interactions section for information concerning beta-blockers and digitalis).

- Mild bradycardia.

- Patients with reduced left ventricular function.

- Renally impaired patients.

- 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.

Diltiazem undergoes biotransformation by the hepatic cytochrome P-450 mixed function oxidase system. The principal isoenzyme involved is CYP3A4. Hence, co-administration with other agents that are also substrates for CYP3A4 may result in competitive inhibition of the metabolism of the concomitant agent.

Simultaneous administration with enzyme inducers such as rifampicin and phenobarbital may lead to reduced activity of diltiazem.

Diltiazem hydrochloride should only be administered with great care to patients receiving concurrent treatment with antihypertensives or other hypotensive agents including halogenated anaesthetics or drugs with moderate protein binding.

Diltiazem hydrochloride will not protect against effects of withdrawal of ß-adrenoceptor blocking agents, nor the rebound effects seen with various antihypertensives. Combination with ß-adrenoceptor blockers having a significant “first pass” loss, e.g. propranolol may require a decrease in their dose and may lead to bradycardia. There may be an additive effect when used with drugs which may induce bradycardia or with other antihypertensives. Concomitant H₂ antagonist therapy may increase diltiazem blood levels.

Diltiazem may affect the blood levels of concomitant carbamazepine, theophylline, ciclosporin and digoxin. Careful attention should therefore be given to signs of overdosage. The levels should be determined and the dose of carbamazepine, theophylline, ciclosporin, or digoxin reduced if necessary. Patients receiving ß-blockers, diuretics, ACE inhibitors or other antihypertensive agents should be regularly monitored. Use with alpha blockers should be strictly monitored.

The simultaneous administration of diltiazem with drugs such as ß-blockers, antiarrhythmics or heart glycosides may cause a greater degree of AV blocking, reduce the heart rate or induce a hypotensive effect. Intravenous administration of ß-blockers should be discontinued during therapy with diltiazem.

Anaesthetists should be warned that a patient is on a calcium antagonist. The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anaesthetics may be potentiated by calcium channel blockers. When used concomitantly, anaesthetics and calcium channel blockers should be titrated carefully.

There have been reports in the literature of diltiazem interactions with warfarin and lithium.

Cautious use with simvastatin and atorvastatin at the lowest effective dose, with patient monitoring for signs and symptoms of rhabdomyolysis, is recommended when co-administration with diltiazem is considered.

There is an increased risk of bradycardia, AV block and myocardial depression when diltiazem and amiodarone are given together.

Diltiazem must not be taken during pregnancy as experimental studies have shown indications of teratogenicity. There is no experience of its effects in humans. As diltiazem is known to enter the breast milk and there is no experience of possible effects in infants, infants should be weaned if treatment of the mother with diltiazem is necessary.

Not applicable.

In studies carried out to date, serious adverse reactions with diltiazem have been rare; however, it should be recognised that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies.

In 900 patients with hypertension, the most common adverse events were oedema (9%), headache (8%), dizziness (6%), asthenia (5%), sinus bradycardia (3%), flushing (3%), and first degree AV block (3%). Only oedema and perhaps bradycardia were dose related. The most common adverse events (>1%) observed in clinical studies of over 2100 angina and hypertensive patients receiving diltiazem were: oedema (5.4%), headache (4.5%), dizziness (3.4%), asthenia (2.8%), first-degree AV block (1.8%), flushing (1.7%), nausea (1.6%), bradycardia (1.5%) and rash (1.5%).

Less common adverse events have included the following:

Cardiovascular: angina, arrhythmia, AV block (second or third degree), congestive heart failure, hypotension, palpitations, syncope.

Nervous system: amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paraesthesia, personality change, somnolence, tinnitus, tremor.

Gastrointestinal: anorexia, constipation, diarrhoea, dyspepsia, mild elevations of alkaline phosphatase, SGOT, SGPT and LDH (see Special Warnings and Precautions), vomiting, weight increase, gingivitis and gingival hypertrophy.

Dermatologic: petechiae, pruritus, photosensitivity, urticaria, Stevens-Johnson syndrome. Allergic skin reactions including erythema multiforme, vasculitis, lymphadenopathy and eosinophilia have been observed in isolated cases. Dermatological events may be transient and may disappear despite continued use of diltiazem. Should a dermatologic reaction persist, the drug should be discontinued.

Other: amblyopia, CK elevation, dyspnoea, epistaxis, eye irritation, hyperglycaemia, nasal congestion, nocturia, osteoarticular pain, muscle pain, polyuria, sexual difficulties, thrombocytopenia, gynaecomastia.

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. 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 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.

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: 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. N-monodesmethyl diltiazem is the predominant metabolite followed quantitatively by the desacetyl metabolite, which has some pharmacological activity. 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. 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 a 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:

Gelatin

Titanium dioxide (E171)

The printing ink contains:

Shellac

Black iron oxide (E172)

Propylene glycol (E1520)

Not applicable.

Two years from the date of manufacture.

Do not store above 25^oC. Store in the original package.

Jaysquare container, containing 7, 20, 30, 50, 60 or 100 capsules.

PVC/PVDC blister pack, containing 4, 28 or 30 capsules.

Not applicable.

Cephalon Limited

1 Albany Place

Hyde Way

Welwyn Garden City

Hertfordshire

AL7 3BT

Dilzem XL 120 mg – PL 21799/0003

Dilzem XL 180 mg – PL 21799/0004

Dilzem XL 240 mg – PL 21799/0005

30 January 2006

August 2009

POM