Therapeutic Index

Each tablet contains:
Diltiazem Tablets

COMPOSITION :
Cardisec-La
Each film-coated tablet contains:
Diltiazem Hydrochloride IP….. 30 mg
Excipients….qs

DOSAGE  FORM :
Tablet

DOSAGE AND ADMINISTRATION :
Exertional Angina Pectoris Due to Atherosclerotic Coronary Artery Disease or Angina Pectoris at Rest Due to Coronary Artery Spasm
Dosage must be adjusted to each patient`s needs. Starting with 30 mg four times daily, before meals and at bedtime, dosage should be increased gradually (given in divided doses three or four times daily) at one- to two-day intervals until optimum response is obtained. Although individual patients may respond to any dosage level, the average optimum dosage range appears to be 180 to 360 mg/day. There are no available data concerning dosage requirements in patients with impaired renal or hepatic function. If the drug must be used in such patients, titration should be carried out with particular caution.

CONTRAINDICATIONS :
* 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
* Hypotension (< 90 mm Hg systolic)
* Hypersensitivity to the drug
* Acute myocardial infarction and pulmonary congestion documented by x-ray on admission

PHARMACOLOGY  :
Pharmacodynamics
Diltiazem is a calcium antagonist. It inhibits the transmembrane influx of extra-cellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells thus causing vasodilation of coronary arteries to a greater extent and peripheral vessels to a lesser extent. Diltiazem also causes a modest decrease in systemic blood pressure, a decrease in afterload of the heart and at high doses, an increase in cardiac index.

Diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and in exercise tolerance studies in patients with ischemic heart disease, reduces heart rate-blood pressure product for any given workload.

In hypertensive patients, diltiazem hydrochloride (HCl) produces anti-hypertensive effects both in the supine and standing positions. Postural hypotension is infrequently noticed upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects. Diltiazem HCl decreases vascular resistance, increases cardiac output by increasing stroke volume, and produces slight decrease or no change in heart rate. Chronic therapy with diltiazem HCl produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem HCl reduces or antagonizes the renal and peripheral effects of angiotensin II.

Chronic oral administration of diltiazem HCl to patients in doses of up to 240 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation.

Pharmacokinetics
Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect. After oral adminstration, diltiazem HCl undergoes extensive metabolism in man by deacetylation-N-demethylation, and O-demethylation via cytochrome P-450 (oxidative metabolism) in addition to conjugation. Metabolites N-monodesmethyldiltiazem, desacetyldiltiazem, desacetyl-N-monodesmethyl-diltiazem, desacetyl-O-desmethyldiltiazem and desacetyl-N, O-desmethyldiltiazem have been identified in human urine. Following oral administration, 2% to 4% of the unchanged diltiazem HCl appears in urine.

The two primary metabolites of diltiazem are desacetyldiltiazem and desmethyldiltiazem. The desacetyl metabolite is approximately 25 to 50% as potent a coronary vasodilator as diltiazem and is present in plasma at concentrations of 10 % to 20% of parent diltiazem. However, recent studies employing sensitive and specific analytical methods have confirmed the existence of several sequential metabolic pathways of metabolism. As many as nine diltiazem metabolites have been identified in urine of humans. Total radioactivity measurements following single intravenous dose administration in healthy volunteers suggest the presence of other unidentified metabolites. These metabolites are excreted more slowly, (with a half-life of total radioactivity of approximately 20 hours) and attain concentrations in excess of diltiazem.

In vitro binding studies show that diltiazem HCl is 70% to 80% bound to plasma proteins. In vitro studies suggest alpha-acid glycoprotein binds approximately 40% of the drug at clinically significant concentrations. Albumin appears to bind approximately 30% of the drug, while other constituents bind the remaining bound fraction. Competitive in vitro ligand binding studies have also shown that diltiazem HCl binding is not altered by therapeutic concentrations of digoxin, hydrochlorthiazide, indomethacin, phenylbutazone, propranolol, salicylic acid, tolbutamide, or warfarin.

Diltiazem is absorbed from the tablet formulation to about 98% of a reference solution. Single oral doses of 30 to 120 mg of diltiazem HCl result in detectable plasma levels within 30 to 60 minutes and peak plasma levels 2 to 4 hours after drug administration. As the dose of diltiazem HCl tablets is increased from a daily dose of 120 mg (30 mg qid) to 240 mg (60 mg qid) daily, there is an increase in area-under-the-curve of 2.3 times. When the dose is increased from 240 mg to 360 mg daily, there is an increase in area-under-the- curve of 1.8 times. The plasma elimination half-life following single or multiple drug administration is approximately 3 to 4.5 hours. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 40 or 50 to 200 ng/ml. There is a departure from linearity when the dose strengths are increased; the half-life is slightly increased with dose. When single doses above 60 mg are given, a 120 mg dose gave blood levels 3 times that of the 60 mg dose.

UNDESIRABLE EFFECTS :
The drug is generally well tolerated. Occasional undesirable effects are nausea, finger swelling, headache, skin rashes and peripheral oedema. Bradycardia and first-degree heart block may also be encountered.

PACKAGING INFORMATION :
Cardisec-La -30 Blister pack of 10 tablets

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