CONTRAINDICATIONS: Verapamil HCl tablets are contraindicated in:

     1. Severe left ventricular dysfunction

2. Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock

3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)

4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker)

5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract

6. Patients with known hypersensitivity to verapamil hydrochloride.

CLINICAL PHARMACOLOGY:

Verapamil HCl is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) that exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductive and contractile myocardial cells.

Mechanism of action

Angina: The precise mechanism of action of Verapamil HCl as an antianginal agent remains to be fully determined, but includes the following two mechanisms:

1. Relaxation and prevention of coronary artery spasm

2. Reduction of oxygen utilization

Arrhythmia: Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, Verapamil HCl prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner. This property accounts for the ability of Verapamil HCl to slow the ventricular rate in patients with chronic atrial flutter or atrial fibrillation.

Essential hypertension: Verapamil HCl exerts anti-hypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachy-cardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%).

Pharmacokinetics and metabolism: Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. A nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist. The mean elimination half-life in single-dose studies ranged from 2.8 to 7.4 hours. In these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). In healthy men, orally administered Verapamil HCl undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except nor-verapamil are present in trace amounts only. Norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. The cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. Approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours; the volume of distribution is increased and plasma clearance reduced to about 30% of normal.

Hemodynamics and myocardial metabolism:

Verapamil HCl reduces afterload and myocardial contractility. Improved left ventricular diastolic function in patients with IHSS and those with coronary heart disease has also been observed with Verapamil HCl therapy

WARNINGS:

Heart failure: Verapamil has a negative inotro-pic effect, which in most patients is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance.

Hypotension: Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels, which may result in dizziness or symptomatic hypotension.

Elevated liver enzymes: Elevations of trans-aminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported.

Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine): Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis).

Atrioventricular block: The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms.

Patients with hypertrophic cardiomyopathy (IHSS): In patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen.

PRECAUTIONS:

Use in patients with impaired hepatic function:

Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function.

Use in patients with attenuated (decreased) neuromuscular transmission: It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

Use in patients with impaired renal function:

Verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage.

 Pregnancy: Pregnancy Category C.

Nursing mothers: Because of the potential for adverse reactions in nursing infants from verap-amil, nursing should be discontinued while verapamil is administered.

Drug Interactions:

Alcohol: Verapamil may increase blood alcohol concentrations and prolong its effects.

Beta-blockers: Controlled studies in small numbers of patients suggest that the concomitant use of Verapamil HCl and oral beta-adrenergic blocking agents may be beneficial in certain patients with chronic stable angina or hypertension, but available information is not sufficient to predict with confidence the effects of concurrent treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil.

Digitalis: Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. However, chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity.

Antihypertensive agents: Verapamil administered concomitantly with oral antihypertensive agents (eg, vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure.

Antiarrhythmic agents:

Disopyramide: disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Flecainide: Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

Quinidine: combined therapy of verap-amil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided.

Other:

Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions.

Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied.

Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy.

Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy.

Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Phenobarbital: Phenobarbital therapy may increase verapamil clearance.

Cyclosporin: Verapamil therapy may increase serum levels of cyclosporin.

Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of the-ophylline.

Inhalation anesthetics: When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should each be titrated carefully to avoid excessive cardiovascular depression.

Neuromuscular blocking agents: It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

SIDE EFFECTS:

Serious adverse reactions are uncommon when Verapamil HCl therapy is initiated with upward dose titration within the recommended single and total daily dose. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions to orally administered verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4,954 patients: Constipation 7.3% Dyspnea 1.4% Dizziness 3.3% Bradycardia 2.7% (HR<50/min) Hypotension 1.4% AV block Headache 2.5% Edema 1.9% CHF, Pulmonary edema 1.2% Flushing 0.6% Fatigue 1.7%.

Treatment of acute cardiovascular adverse reactions: The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately; eg, intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol HCl (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine HCl, metaraminol bitar-trate, or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, dopamine HCl or dobu-tamine HCl may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

OVERDOSAGE:

Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially Verapamil HCl SR), preferably under continuous hospital care.

Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including cardiopulmonary resuscitation.

DOSAGE AND ADMINISTRATION:

 The usefulness and safety of dosages exceeding 480 mg/day have not been established. Since the half-life of verapamil increases during chronic dosing, maximum response may be delayed.

Angina: Clinical trials show that the usual dose is 80 mg to 120 mg three times a day. Dosage may be increased at daily (eg, patients with unstable angina) or weekly intervals until optimum clinical response is obtained.

Arrhythmias: The dosage in digitalized patients with chronic atrial fibrillation ranges from 240 to 320 mg/day in divided (t.i.d. or q.i.d.) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (t.i.d. or q.i.d.) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy.

Essential hypertension: The usual initial mono-therapy dose in clinical trials was 80 mg three times a day (240 mg/day). The antihypertensive effects of Verapamil HCl are evident within the first week of therapy.

How Supplied: Each Package of Ruz-Verapamil 40mg or 80mg tablets contains 100 Tablets in a bottle. Store at controlled room temperature 15° to 25°C and protect from light, Dispense in tight, light-resistant containers.

Reference: USPDI for Professional Health Care, 2004, Page 667-683

                  Martindale 2005, Page 1019-1022

                  PDR 2000, page 2897-9