Label: VERAPAMIL HYDROCHLORIDE injection

Mechanism of Action

Verapamil hydrochloride injection inhibits the calcium ion (and possibly sodium ion) influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells. The antiarrhythmic effect of verapamil hydrochloride injection appears to be due to its effect on the slow channel in cells of the cardiac conduction system. The vasodilatory effect of verapamil hydrochloride injection appears to be due to its effect on blockade of calcium channels as well as α receptors.

In the isolated rabbit heart, concentrations of verapamil hydrochloride injection that markedly affect SA nodal fibers or fibers in the upper and middle regions of the AV node have very little effect on fibers in the lower AV node (NH region) and no effect on atrial action potentials or His bundle fibers.

Electrical activity in the SA and AV nodes depends, to a large degree, upon calcium influx through the slow channel. By inhibiting this influx, verapamil hydrochloride injection slows AV conduction and prolongs the effective refractory period within the AV node in a rate-related manner. This effect results in a reduction of the ventricular rate in patients with atrial flutter and/or atrial fibrillation and a rapid ventricular response.

By interrupting reentry at the AV node, verapamil hydrochloride injection can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias (PSVT), including PSVT associated with Wolff-Parkinson-White syndrome.

Verapamil hydrochloride injection does not induce peripheral arterial spasm.

Verapamil hydrochloride injection 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.

Verapamil hydrochloride injection does not alter total serum calcium levels.

Hemodynamics

Verapamil hydrochloride injection reduces afterload and myocardial contractility. The commonly used intravenous doses of 5 to 10 mg verapamil hydrochloride injection produce transient, usually asymptomatic, reduction in normal systemic arterial pressure, systemic vascular resistance and contractility; left ventricular filling pressure is slightly increased. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil hydrochloride injection is countered by reduction of afterload, and cardiac index is usually not reduced. However, in patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Peak therapeutic effects occur within 3 to 5 minutes after a bolus injection.

Pharmacokinetics

Intravenously administered verapamil hydrochloride injection has been shown to be rapidly metabolized. Following intravenous infusion in man, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about 4 minutes) and a slower terminal elimination phase (half-life 2 to 5 hours). In healthy men, orally administered verapamil hydrochloride injection undergoes extensive metabolism in the liver, 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N- and O- dealkylated products of verapamil hydrochloride injection. Approximately 70% of an administered dose is excreted in the urine and 16% or more in the feces within 5 days. About 3% to 4% is excreted as unchanged drug.

Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in the elderly.

Hypotension

Intravenous verapamil hydrochloride injection often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic but may result in dizziness. Systolic pressure less than 90 mmHg and/or diastolic pressure less than 60 mmHg was seen in 5 to 10% of patients in controlled U.S. trials in supraventricular tachycardia and in about 10% of the patients with atrial flutter/fibrillation. The incidence of symptomatic hypotension observed in studies conducted in the U.S. was approximately 1.5%. Three of the five symptomatic patients required intravenous pharmacologic treatment (levarterenol bitartrate, metaraminol bitartrate, or 10% calcium gluconate). All recovered without sequelae.

Extreme Bradycardia/Asystole

Verapamil hydrochloride injection affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients. Bradycardia associated with sick sinus syndrome was reported in 0.3% of the patients treated in controlled double-blind trials in the United States. The total incidence of bradycardia (ventricular rate less than 60 beats/min) was 1.2% in these studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. (See ADVERSE REACTIONS:Treatment of Acute Cardiovascular Adverse Reactions.)

Heart Failure

When heart failure is not severe or rate related, it should be controlled with digitalis glycosides and diuretics, as appropriate, before verapamil hydrochloride injection is used. In patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mmHg, ejection fraction less than 30%), acute worsening of heart failure may be seen.

Concomitant Antiarrhythmic Therapy

Digitalis: Intravenous verapamil has been used concomitantly with digitalis preparations without the occurrence of serious adverse effects. However, since both drugs slow AV conduction, patients should be monitored for AV block or excessive bradycardia.

Procainamide: Intravenous verapamil has been administered to a small number of patients receiving oral procainamide without the occurrence of serious adverse effects.

Quinidine: Intravenous verapamil has been administered to a small number of patients receiving oral quinidine without the occurrence of serious adverse effects. However, three patients have been described in whom the combination resulted in an exaggerated hypotensive response presumably from the combined ability of both drugs to antagonize the effects of catecholamines on α-adrenergic receptors. Caution should therefore be used when employing this combination of drugs.

Beta-Adrenergic Blocking Drugs: Intravenous verapamil has been administered to patients receiving oral beta blockers without the development of serious adverse effects. However, since both drugs may depress myocardial contractility and AV conduction, the possibility of detrimental interactions should be considered. The concomitant administration of intravenous beta blockers and intravenous verapamil has resulted in serious adverse reactions (see CONTRAINDICATIONS), especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction.

Disopyramide: Until data on possible interactions between verapamil and all forms of disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration.

Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects reducing myocardial contractility, prolonging AV conduction, and prolonging repolarization.

Heart Block

Verapamil hydrochloride injection prolongs AV conduction time. While high degree AV block has not been observed in controlled clinical trials in the U.S., a low percentage (less than 0.5%) has been reported in the world literature. Development of second- or third-degree AV block or unifascicular, bifascicular, or trifascicular bundle branch block requires reduction in subsequent doses or discontinuation of verapamil and institution of appropriate therapy, if needed. (See ADVERSE REACTIONS:Treatment of Acute Cardiovascular Adverse Reactions.)

Hepatic and Renal Failure

Significant hepatic and renal failure should not increase the effects of a single intravenous dose of verapamil hydrochloride injection but may prolong its duration. Repeated injections of intravenous verapamil hydrochloride injection in such patients may lead to accumulation and an excessive pharmacologic effect of the drug. There is no experience to guide use of multiple doses in such patients, and this generally should be avoided. If repeated injections are essential, blood pressure and PR interval should be closely monitored and smaller repeat doses should be utilized. Verapamil cannot be removed by hemodialysis.

Premature Ventricular Contractions

During conversion to normal sinus rhythm, or marked reduction in ventricular rate, a few benign complexes of unusual appearance (sometimes resembling premature ventricular contractions) may be seen after treatment with verapamil hydrochloride injection. Similar complexes are seen during spontaneous conversion of supraventricular tachycardias, after D.C.-cardioversion and other pharmacologic therapy. These complexes appear to have no clinical significance.

Duchenne's Muscular Dystrophy

Intravenous verapamil hydrochloride injection can precipitate respiratory muscle failure in these patients and should, therefore, be used with caution.

Increased Intracranial Pressure

Intravenous verapamil hydrochloride injection has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction. Caution should be taken and appropriate monitoring performed.

Drug Interactions

(See WARNINGS: Concomitant Antiarrhythmic Therapy) Intravenous verapamil hydrochloride injection has been used concomitantly with other cardioactive drugs (especially digitalis) without evidence of serious negative drug interactions. In rare instances, including when patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction were given intravenous beta-adrenergic blocking agents or disopyramide concomitantly with intravenous verapamil, serious adverse effects have occurred. Concomitant use of verapamil hydrochloride injection with β-adrenergic blockers may result in an exaggerated hypotensive response. Such an effect was observed in one study, following the concomitant administration of verapamil and prazosin. It may be necessary to decrease the dose of verapamil and/or dose of the neuromuscular blocking agent when the drugs are used concomitantly. As verapamil is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein bound drugs.

Other

Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. In acute studies of healthy volunteers, clearance of verapamil was either reduced or unchanged.

Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. The addition of verapamil, however, has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.

Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

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.

Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists (such as verapamil) should be titrated carefully to avoid excessive cardiovascular depression.

Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of depolarizing and nondepolarizing 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.

Dantrolene: Two animal studies suggest concomitant intravenous use of verapamil and dantrolene sodium may result in cardiovascular collapse. There has also been one report of hyperkalemia and myocardial depression following the coadministration of oral verapamil and intravenous dantrolene.

Pregnancy

Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

Labor and Delivery

There have been few controlled studies to determine whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil hydrochloride injection in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil hydrochloride injection crosses the placental barrier and can be detected in umbilical vein blood at delivery. Also, verapamil hydrochloride injection is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Pediatrics

Controlled studies with verapamil have not been conducted in pediatric patients, but uncontrolled experience with intravenous administration in more than 250 patients, about half under 12 months of age and about 25% newborn, indicates that results of treatment are similar to those in adults. In rare instances, however, severe hemodynamic side effects – some of them fatal – have occurred following the intravenous administration of verapamil to neonates and infants. Caution should therefore be used when administering verapamil to this group of pediatric patients.

The most commonly used single doses in patients up to 12 months of age have ranged from 0.1 to 0.2 mg/kg of body weight, while in patients aged 1 to 15 years, the most commonly used single doses ranged from 0.1 to 0.3 mg/kg of body weight. Most of the patients received the lower dose of 0.1 mg/kg once but, in some cases, the dose was repeated once or twice every 10 to 30 minutes.