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Endocrine - Metabolic

DENAZOX

COMPOSITION

Each tablet contain

Active ingredient: Diltiazem Hydrochloride: 60mg

Inactive ingredients: Lactose, Starch, Povidone, Methacrylic acid copolymer 30%, Microcrystalline Cellulose, Colloidal Silicon Dioxide, Magnesium Stearate, Talc.

MECHANISM OF ACTION

Diltiazem is a calcium antagonist. It restricts the slow channel entry of calcium into the cell and so reduces the liberation of calcium from stores in the sarcoplasmic reticulum. This results in a reduction of the amount of available intracellular calcium reducing myocardial oxygen consumption. It increases exercise capacity and improves all indices of myocardial ischaemia in the angina patient. Diltiazem relaxes large and small coronary arteries and relieves the spasm of vasospastic (prinzmetals) angina and the response to catecholamines but has little effect on the peripheral vasculature. There is therefore no possibility of reflex tachycardia. A small reduction in heart rate occurs which is accompanied by an increase in cardiac output, improved myocardial perfusion and reduction of ventricular work. In animal studies, Diltiazem protects the myocardium against the effects of ischaemia and reduces the damage produced by excessive entry of calcium into the myocardial cell during reperfusion.

PHARMACOKINETICS

Diltiazem hydrochloride is effective in angina, protecting the heart against ischaemia, vasodilating coronary arteries and reducing myocardial oxygen requirements. It is well tolerated and does not generally give rise to side effects associated with peripheral vasodilators, nor cause significant myocardial depression.

Diltiazem is well absorbed (90%) in healthy volunteers following oral administration.

Peak plasma concentrations occur 3 to 4 hours after dosing.

Due to a first pass effect, the bioavailability of the 60 mg tablet is about 40 %.

The mean apparent plasma half-life is 4 – 8 hours.

Diltiazem is 80 to 85% bound to plasma proteins. It is extensively metabolised by the liver.

The major circulating metabolite, N-monodesmethyl diltiazem accounts for approximately 35% of the circulating diltiazem.

Less than 5% of diltiazem is excreted unchanged in the urine.

There is a linear relationship between dose and plasma concentration. During long term administration to any one patient, plasma concentrations of diltiazem remain constant.

Mean plasma concentrations in elderly subjects and patients with renal and hepatic insufficiency are higher than in young subjects.

Diltiazem and its metabolites are poorly dialysed.

INDICATIONS:

Prophylaxis and treatment of Angina Pectoris.

DOSAGE AND ADMINISTRATION:

 Adults

The usual dose is one tablet (60mg) three times daily. However, patient responses may vary and dosage requirements can differ significantly between individual patients. If necessary the divided dose may be increased to 360mg/day. 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 these high doses.

Elderly and patients with impaired hepatic or renal function

The recommended starting dose is one tablet (60mg) twice daily. The heart rate should be measured regularly in these groups of patients and the dose should not be increased if the heart rate falls below 50 beats per minute.

Children

Safety and efficacy in children have not been established.

CONTRAINDICATIONS:

Sick sinus syndrome, 2nd or 3rd degree AV block in patients without a functioning pacemaker.

Severe bradycardia (less than 50 beats per minute).

Left ventricular failure with pulmonary stasis.

Pregnancy, women of child-bearing potential and lactation (see section 4.6 Pregnancy and lactation).

Concurrent use with dantrolene infusion (see section 4.5 Interactions with other medicinal products and other forms of interactions).

Hypersensitivity to diltiazem or to any of the excipients.

ADVERSE REACTIONS

Cardiovascular disorders:

The manifestations of vasodilation (orthostatic hypotension, headache, flushing and in particular oedema of the lower limbs) are dose-dependent and appear more frequently in elderly subjects and are related to the pharmacological activity of the product.

Occasional cases of vascultitis.

Rare cases of symptomatic bradycardia and sino-atrial block and atrioventricular block, palpitations.

Development or aggravation of congestive heart failure.

Gastro-intestinal system disorders:

Digestive disturbances such as dyspepsia, gastric pain, nausea, constipation, dry mouth.

Gingival hyperplasia

Skin and appendage disorders:

Muco-cutaneous reactions such as simple erythema, urticaria, or occasionally desquamative erythema, with or without fever and photosensitivity have been reported, recovering when the treatment is discontinued.

Erythema multiforme and/or exfoliative dermatitis and acute generalised exanthematous pustular dermatitis have been reported.

Liver and other biliary system disorders:

Isolated cases of moderate and transient elevation of liver transaminases have been observed at the start of treatment. Isolated cases of clinical hepatitis have been reported which resolved on cessation of diltiazem therapy.

Others:

Malaise, dizziness, asthenia/fatigue.

As with some other calcium channel blockers, exceptional cases of extrapyramidal symptoms and gynaecomastia have been reported, reversible after discontinuation of calcium antagonists.

Inform doctors with side effects when using medicine.

PRECAUTIONS:

Close observation is necessary in patients with reduced left ventricular function, 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.

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.

In the case of general anaesthesia, the anaesthetist must be informed that the patient is taking diltiazem. The depression of cardiac contractility, conductivity and automaticity as well as the vascular dilatation associated with anaesthetics may be potentiated by calcium channel blockers.

USE IN PREGNANCY

Pregnancy

This drug has been shown to be teratogenic in certain animal species and is therefore contraindicated in pregnancy and in women of child-bearing potential.

Breast feeding

As this drug is excreted in breast milk, breast feeding whilst taking diltiazem is contraindicated.

DRUG INTERACTIONS

Combination contraindicated for safety reasons:

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 Contraindications).

Combinations requiring caution:

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 strict monitoring of blood pressure.

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.

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.

Antiarrhythmic agents: Since diltiazem has antiarrhythmic properties, its concomitant prescription with other antiarrhythmic agents is not recommended due to the risk of increased cardiac adverse effects due to an additive effect. This combination should only be used under close clinical and ECG monitoring.

Nitrate derivatives: Increased hypotensive effects and faintness (additive vasodilating effects).

In all patients treated with calcium antagonists, the prescription of nitrate derivatives should only be carried out at gradually increasing doses.

Cyclosporin: 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.

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.

Theophylline: Increase in circulating theophylline levels.

Anti-H2 agents (cimetidine and 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.

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.

Lithium: Risk of increase in lithium-induced neurotoxicity.

Combinations to be taken into account:

Oral administration of diltiazem can raise the plasma concentration of drugs exclusively metabolised by CYP3A4. The concomitant therapy of diltiazem and such drugs may increase the risk of adverse reactions (e.g. muscular disorders with statins).

OVERDOSE

The clinical effects of acute overdose can involve pronounced hypotension leading to collapse, sinus bradycardia with or without isorhythmic dissociation, and atrioventricular conduction disturbances.

Treatment, under hospital supervision, will include gastric lavage, osmotic diuresis. Conduction disturbances may be managed by temporary cardiac pacing.

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

STORAGE CONDITIONS: Store at temperature below 250C. Protect from sunlight and moisture.

SHELF-LIFE: 5 years from the manufacturing date.

HOW SUPPLIED: 5 blisters x 10 Tablets/Box.

SPECIFICATION: USP

WARNING:

  • Read carefully the leaflet before use.
  • For further information, please contact your doctor.
  • This drug is dispensed on prescription only.
  • Keep out of reach of children.

MANUFACTURED by:

REMEDICA  LTD

Limassol Industrial Estate, Aharnon Street, P.O. Box 51706, 3508 Limassol, Cyprus, Europe.

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