VERAPAMIL HCL- verapamil hydrochloride injection
AMERICAN REGENT, INC.
Verapamil HCl is a calcium antagonist or slow channel inhibitor. Verapamil Hydrochloride is available in 5 mg/2 mL single dose vials (for intravenous administration). Each mL contains Verapamil HCI 2.5 mg, Sodium Chloride 8.5 mg and Water for Injection q.s. pH adjusted with Hydrochloric Acid and/or Sodium Hydroxide. The pH of the solution is between 4 and 6.5. Protect contents from light. Sterile, nonpyrogenic.
The structural formula of Verapamil HCI is given below:
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 antiarrhythmic drugs.
Mechanism of Action: Verapamil 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 appears to be due to its effect on the slow channel in cells of the cardiac conduction system. The vasodilatory effect of verapamil 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 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 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 can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias (PSVT), including PSVT associated with Wolff-Parkinson-White syndrome.
Verapamil does not induce peripheral arterial spasm.
Verapamil 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 does not alter total serum calcium levels.
Hemodynamics: Verapamil reduces afterload and myocardial contractility. The commonly used intravenous doses of 5 to 10 mg verapamil hydrochloride 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 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 has been shown to be rapidly metabolized. Following intravenous infusion in man, verapamil is eliminated biexponentially, 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 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 0-dealkylated products of verapamil. 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.
Intravenous Verapamil HCI is indicated for the following:
- Rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, including those associated with accessory bypass tracts (Wolff-Parkinson-White [W-P-W] and Lown-Ganong-Levine [L-G-L] syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to verapamil hydrochloride administration.
- Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff-Parkinson-White [W-P-W] and Lown-Ganong-Levine [L-G-L] syndromes).
In controlled studies in the United States, about 60% of patients with supraventricular tachycardia converted to normal sinus rhythm within 10 minutes after intravenous verapamil. Uncontrolled studies reported in the world literature describe a conversion rate of about 80%. About 70% of patients with atrial flutter and/or fibrillation with a fast ventricular rate respond with a decrease in ventricular rate of at least 20%. Conversion of atrial flutter or fibrillation to sinus rhythm is uncommon (about 10%) after verapamil and may reflect the spontaneous conversion rate, since the conversion rate after placebo was similar. Slowing of the ventricular rate in patients with atrial fibrillation/flutter lasts 30 to 60 minutes after a single injection.
Because a small fraction (<1%) of patients treated with verapamil respond with life-threatening adverse responses (rapid ventricular rate In atrial flutter/fibrillation and an accessory bypass tract, marked hypotension, or extreme bradycardia/asystole — see Contraindications and Warnings), the initial use of intravenous verapamil should, if possible, be in a treatment setting with monitoring and resuscitation facilities, including DC-cardioversion capability (see Suggested Treatment of Acute Cardiovascular Adverse Reactions). As familiarity with the patient’s response is gained, use in an office setting may be acceptable.
Cardioversion has been used safely and effectively after intravenous verapamil.
Intravenous Verapamil HCI is contraindicated in:
- Severe hypotension or cardiogenic shock.
- Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
- Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).
- Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy.)
- Patients receiving intravenous beta adrenergic blocking drugs (e.g., propranolol). Intravenous verapamil and intravenous beta adrenergic blocking drugs should not be administered in close proximity to each other (within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction.
- Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (i.e. Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil is administered. Therefore, the use of verapamil in these patients is contraindicated.
- Ventricular Tachycardia. Administration of intravenous verapamil to patients with wide-complex ventricular-tachycardia (QRS ≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting.
- Known hypersensitivity to verapamil hydrochloride.
VERAPAMIL HYDROCHLORIDE SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO MINUTE PERIOD OF TIME. (See DOSAGE AND ADMINISTRATION)
Hypotension: Intravenous Verapamil HCI 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 mm Hg and/or diastolic pressure less than 60 mm Hg 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 (norepinephrine bitartrate, metaraminol bitartrate, or 10% calcium gluconate). All recovered without sequelae.
Extreme Bradycardia/Asystole: Verapamil HCI 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 and 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 is used. 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.
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