Verapamil Information
Verapamil ()
Verapamil () Description
Verapamil () hydrochloride extended-release tablet USP is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verapamil () hydrochloride extended-release tablet USP is available for oral administration as brown colored oval, biconvex, film-coated tablets containing 120 mg Verapamil () hydrochloride USP and as brown colored oval, biconvex, film-coated tablets containing 180 mg Verapamil () hydrochloride USP. 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 () HCl USP is given below:
CHNO·HCl
M.W. 491.06
Benzeneacetronitrile, α[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4- dimethoxy-α-(1-methylethyl) hydrochloride
Verapamil () HCl USP is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil () HCl USP is not chemically related to other cardioactive drugs.
In addition to Verapamil () HCl USP, the Verapamil () hydrochloride extended-release tablet USP contains the following ingredients: colloidal silicon dioxide, sodium alginate, hypromellose, magnesium stearate, microcrystalline cellulose, povidone, polyethylene glycol and titanium dioxide. The following are the color additives per tablet strength:
Strength (mg) Color Additive(s)
120 Ferric Oxide Yellow, Ferric Oxide Red and Ferric Oxide Black
180 Ferric Oxide Yellow, Ferric Oxide Red and Ferric Oxide Black
Verapamil () hydrochloride extended-release tablets USP, 120 mg and 180 mg meet USP Drug Release Test 1.
Verapamil () Clinical Pharmacology
Verapamil () hydrochloride 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.
With the immediate release formulation, more than 90% of the orally administered dose of Verapamil () hydrochloride is absorbed. 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. Chronic oral administration of 120 mg of Verapamil () hydrochloride every 6 hours resulted in plasma levels of Verapamil () ranging from 125 to 400 ng/mL with higher values reported occasionally. A nonlinear correlation between the Verapamil () dose administered and Verapamil () plasma levels does exist.
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 Verapamil () hydrochloride extended-release was similar to Verapamil () hydrochloride (immediate release); rates of absorption were, of course, different. In a randomized, single-dose, crossover study using healthy volunteers, administration of 240 mg Verapamil () hydrochloride extended-release with food produced peak plasma Verapamil () concentrations of 79 ng/mL, time to peak plasma Verapamil () concentration of 7.71 hours, and AUC of 841 ng-hr/mL. When Verapamil () hydrochloride extended-release 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 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 Verapamil () hydrochloride extended-release have shown effectiveness of doses similar to the effective doses of Verapamil () hydrochloride (immediate release).
In healthy man, orally administered Verapamil () hydrochloride 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 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. 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 ); 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 ).
Verapamil () Indications And Usage
Verapamil () hydrochloride extended-release tablets USP are indicated for the management of essential hypertension.
Verapamil () Contraindications
Verapamil () hydrochloride is contraindicated in:
Verapamil () Warnings
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). Although a risk of this occurring with oral Verapamil () has not been established, such patients receiving oral Verapamil () may be at risk and its use in these patients is contraindicated (see ).
Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral Verapamil () hydrochloride.
Verapamil () Precautions
Telethromycin:
Clonidine :
Aspirin:
Grapefruit juice:
Beta-Blockers:
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 () .
A decrease in metoprolol and propranolol clearance has been observed when either drug is administered concomitantly with Verapamil () . A variable effect has been seen when Verapamil () and atenolol were given together.
Digitalis
Antihypertensive Agents
Antiarrhythmic Agents:
Disopyramide
Flecainide:
Quinidine:
The electrophysiological effects of quinidine and Verapamil () on AV conduction were studied in 8 patients. Verapamil () significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during Verapamil () therapy.
Nitrates:
Other
Cimetidine: The interaction between cimetidine and chronically administered Verapamil () has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers: clearance of Verapamil () was either reduced or unchanged.
Lithium:
Carbamazepine:
Rifampin:
Phenobarbital:
Cyclosporine:
Theophylline:
Inhalation Anesthetics:
Neuromuscular Blocking Agents:
An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of Verapamil () administered in the diet of rats for two years at doses of 10, 35, and 120 mg/kg per day or approximately 1x, 3.5x, and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day).
Verapamil () was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation.
Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.
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% 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 (1º, 2º, 3º) 1.2%
Headache 2.2% 2º and 3º 0.8%
Edema 1.9% Rash 1.2%
CHF/Pulmonary 1.8% Flushing 0.6%
Edema
Elevated Liver Enzymes (see )
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% 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.
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, e.g., intravenously administered isoproterenol HCl, norepinephrine bitartrate, atropine sulfate (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate 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 dobutamine 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.
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 observations for at least 48 hours [especially Verapamil () hydrochloride extended-release] 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 Verapamil () hydrochloride extended-release 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.
Verapamil () How Supplied
Verapamil () hydrochloride extended-release tablets USP, 120 mg are supplied as brown colored oval, biconvex, film-coated tablets with ‘292’ debossed on one side and plain on the other side.
120 mg (brown colored) – Bottles of 90
NDC # 68462-292-90
Bottles of 100
NDC # 68462-292-01
Bottles of 500
NDC # 68462-292-05
Verapamil () hydrochloride extended-release tablets USP, 180 mg are supplied as brown colored oval, biconvex, film-coated tablets with ‘293’ debossed on one side and breakline on the other side.
180 mg (brown colored) – Bottles of 90
NDC # 68462-293-90
Bottles of 100
NDC # 68462- 293 - 01
Bottles of 500
NDC # 68462-293-05
Verapamil ()
Verapamil () Package/label Principal Display Panel
Verapamil ()
