Isoptin Sr Information
Isoptin sr (Verapamil) Description
Isoptin sr (Verapamil) (verapamil hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Isoptin sr (Verapamil) is available for oral administration as light green, capsule shaped, scored, film-coated tablets containing 240 mg verapamil hydrochloride, as light pink, oval shaped, scored, film-coated tablets containing 180 mg verapamil hydrochloride, and as light violet, oval shaped, film-coated tablets containing 120 mg verapamil hydrochloride. The tablets are designed for sustained release of the drug in the gastrointestinal tract, sustained release characteristics are not altered when the tablet is divided in half.
The structural formula of verapamil HCI is given below:
CHNO•HCl M.W. 491.08
Benzeneacetronitrile, α [3-[[2-(3, 4-dimethoxyphenyl) ethyl] methylamino] propyl]-3, 4- dimethoxy-α-(1-methylethyl) hydrochloride
Verapamil HCI is an almost white, crystalline powder, practically free of odor, with a bitter taste.
It is soluble in water, chloroform and methanol. Verapamil HCI is not chemically related to other cardioactive drugs.
In addition to verapamil HCI, the Isoptin sr (Verapamil) tablet contains the following ingredients: alginate, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polyvinyl pyrrolidone, talc, and titanium dioxide. The following are the color additives per tablet strength:
Strength (mg) Color Additive(s)
120 Iron Oxide
180 Iron Oxide
240 D&C yellow #10 Lake dye, and FD&C blue #2 Lake dye
Isoptin sr (Verapamil) Clinical Pharmacology
ISOPTIN (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 conductile and contractile myocardial cells.
ISOPTIN exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise ISOPTIN does not alter systolic cardiac function in patients with normal ventricular function. ISOPTIN does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of ISOPTIN.
ISOPTIN (verapamil HCI) dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm, and is responsible for the effectiveness of ISOPTIN in vasospastic (Prinzmetal’s or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina.
ISOPTIN regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles.
Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, ISOPTIN prolongs the effective refractory period within the AV node and slows AV conduction in a rate related manner.
Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, ISOPTIN may interfere with sinus node impulse generation and may induce sinus arrest or sinoatrial block.
Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS).
ISOPTIN does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. ISOPTIN may shorten the antegrade effective refractory period of accessory bypass tracts. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS).
ISOPTIN has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis.
It is not known whether this action is important at the doses used in man.
In early dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the PR interval. However, during chronic administration this relationship may disappear. 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). Half-life of verapamil may increase during titration. No relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure.
Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly.
In multiple dose studies under fasting conditions the bioavailability measured by AUC of Isoptin sr (Verapamil) was similar to ISOPTIN immediate release; rates of absorption were, of course, different. In a randomized, single-dose, crossover study using healthy volunteers, administration of 240 mg Isoptin sr (Verapamil) with food produced peak plasma verapamil concentrations of 79 ng/mL, time to peak plasma verapamil concentration of 7.71 hours, and AUC (0-24 hr) of 841 ng-hr/mL. When Isoptin sr (Verapamil) was administered to fasting subjects, peak plasma verapamil concentration was 164 ng/mL; time to peak plasma verapamil concentration was 5.21 hours; and AUC (0-24 hr) was 1,478 ng-hr/mL. Similar results were demonstrated for plasma norverapamil. Food thus produces decreased bioavailability (AUC) but a narrower peak to trough ratio. Good correlation of dose and response is not available, but controlled studies of Isoptin sr (Verapamil) have shown effectiveness of doses similar to the effective doses of ISOPTIN (immediate release).
In healthy man, orally administered ISOPTIN undergoes extensive metabolism in the liver. Twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. Norverapamil can reach steadystate 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. About 3% to 4% is excreted in the urine as unchanged drug. Approximately 90% is bound to plasma proteins. In patients with hepatic insufficiency, metabolism of immediate release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours (see PRECAUTIONS); the volume of distribution is increased and plasma clearance reduced to about 30% of normal. Verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one third of the oral daily dose required for patients with normal liver function.
After four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil.
In ten healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg) resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg•hr/dL) compared to placebo. The area under the blood ethanol concentration versus time curve (AUC over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg•hr/dL). Verapamil AUCs were positively correlated (r=0.71) to increased ethanol blood AUC values. (See PRECAUTIONS: Drug Interactions.)
Isoptin sr (Verapamil) Indications And Usage
Isoptin sr (Verapamil) (verapamil HCI) is indicated for the management of essential hypertension.
Isoptin sr (Verapamil) Contraindications
Verapamil HCI is contraindicated in:
1. Severe left ventricular dysfunction (see WARNINGS)
2. Hypotension (systolic pressure less than 90 mmHg) 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 (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (see WARNINGS).
6. Patients with known hypersensitivity to verapamil hydrochloride.
Isoptin sr (Verapamil) Warnings
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral ISOPTIN.
Isoptin sr (Verapamil) Adverse Reactions
Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. 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%
Fatigue 1.7%
Dizziness 3.3%
Dyspnea 1.4%
Nausea 2.7%
Bradycardia (HR
Hypotension 2.5%
AV Block-total (1 °, 2 °, 3 °) 1.2%
Headache 2.2%
2 ° and 3 ° 0.8%
Edema 1.9%
Rash 1.2%
CHF/Pulmonary Edema 1.8%
Flushing 0.6%
Elevated Liver Enzymes (see WARNING)
In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.
The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship.
Isoptin sr (Verapamil) Overdosage
Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (e.g., junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident.
Treat all verapamil overdoses as serious and maintain observation for at least 48 hours [especially Isoptin sr (Verapamil) (verapamil hydrochloride)] preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained release formulation. Verapamil is known to decrease gastrointestinal transit time.
In overdose, tablets of Isoptin sr (Verapamil) have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged.
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. Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. 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.
Isoptin sr (Verapamil) Dosage And Administration
The dose of Isoptin sr (Verapamil) should be individualized by titration and the drug should be administered with food. Initiate therapy with 180 mg of sustained-release verapamil HCI, Isoptin sr (Verapamil) , given in the morning. Lower, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., the elderly or small people etc.). Upward titration should be based on therapeutic efficacy and safety evaluated weekly and approximately 24 hours after the previous dose. The antihypertensive effects of Isoptin sr (Verapamil) are evident within the first week of therapy.
If adequate response is not obtained with 180 mg of Isoptin sr (Verapamil) , the dose may be titrated upward in the following manner:
a) 240 mg each morning,
b) 180 mg each morning plus 180 mg each evening, or 240 mg each morning plus 120 mg each evening
c) 240 mg every twelve hours.
When switching from immediate release ISOPTIN to Isoptin sr (Verapamil) , the total daily dose in milligrams may remain the same.
Isoptin sr (Verapamil) How Supplied
Isoptin sr (Verapamil) 240 mg tablets are supplied as light green, capsule shaped, scored, film-coated tablets containing 240 mg of verapamil hydrochloride. The tablet is embossed with “pp” on one side and “ST” on the other side. Isoptin sr (Verapamil) 180 mg tablets are supplied as light pink, oval shaped, scored, film-coated tablets containing 180 mg of verapamil hydrochloride. The tablet is embossed with “pp” on one side, and “SK” on the other side. The Isoptin sr (Verapamil) 120 mg tablets are supplied as light violet, oval shaped, film-coated tablets containing 120 mg of verapamil hydrochloride. The tablet is embossed with “p” on one side and “SC” on the other side.
240 mg (light green) -Bottle of 100-NDC # 10631-490-01
Bottle of 500- NDC # 10631-490-05
180 mg (light pink) -Bottle of 100- NDC # 10631-489-01
120 mg (light violet) -Bottle of 100- NDC # 10631-488-01
Protect from light and moisture.
Dispense in a tight, light-resistant container as defined in the USP.
Manufactured by:
North Chicago, IL 60064 USA
Manufactured for:
Charlotte, NC 28210 USA
January 2005
