Verapamil hydrochloride is a calcium antagonist or slow-channel inhibitor available as a sterile solution for intravenous injection in 5-mg (2 ml) and 10-mg (4 ml) vials. Each form contains Verapamil HCl 2.5 mg/ml and sodium chloride 8.5 mg/ml in water for injection. Hydrochloric acid and/or sodium hydroxide is used for pH adjustment. The pH of the solution is between 4.1 and 6.0.

The structural formula of verapamil HCl is given below:

Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride

Verapamil hydrochloride is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform, and methanol. Verapamil hydrochloride is not chemically related to other antiarrhythmic drugs. 

Verapamil is indicated for the treatment of supraventricular tachyarrhythmias, including:

•

Rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, including those associated with accessory bypass tracts (Wolff-Parkinson-White [WPW] and Lown-Ganong-Levine [LGL] syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to Verapamil 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 [WPW] and Lown-Ganong-Levine [LGL] syndromes).

In controlled studies in the U.S., about 60% of patients with supraventricular tachycardia converted to normal sinus rhythm within 10 minutes after intravenous Verapamil hydrochloride. 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 heart rate of at least 20%. Conversion of atrial flutter or fibrillation to sinus rhythm is uncommon (about 10%) after Verapamil hydrochloride and may reflect the spontaneous conversion rate, since the conversion rate after placebo was similar. The effect of a single injection lasts for 30–60 minutes when conversion to sinus rhythm does not occur.

Because a small fraction (<1.0%) of patients treated with Verapamil hydrochloride respond with life-threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation with an accessory bypass tract, marked hypotension, or extreme bradycardia/asystole—see Contraindications and Warnings), the initial use of intravenous Verapamil hydrochloride 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, an office setting may be acceptable.

Cardioversion has been used safely and effectively after intravenous Verapamil.

Verapamil hydrochloride injection is contraindicated in:

1.

Severe hypotension or cardiogenic shock

2.

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

3.

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

4.

Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to Verapamil therapy)

5.

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.

6.

Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if Verapamil is administered.

7.

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.

8.

Known hypersensitivity to Verapamil hydrochloride

VERAPAMIL SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME. (See Dosage and Administration.)

Hypotension:  Intravenous Verapamil 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%-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 pharmacologic treatment (norepinephrine bitartrate IV, metaraminol bitartrate IV, or 10% calcium gluconate IV). All recovered without sequelae.

Extreme bradycardia/asystole:  Verapamil 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 U.S. 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 including suggested treatment of 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.

Drug interactions:  (See Warnings: Concomitant antiarrhythmic therapy.) Intravenous Verapamil has been used concomitantly with other cardioactive drugs (e.g., 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 with agents that decrease adrenergic function may result in an exaggerated hypotensive response. Animal studies suggest concomitant use of intravenous Verapamil and intravenous dantrolene sodium may result in cardiovascular collapse. The clinical relevance of these findings is unknown.

Cimetidine has no effect on intravenous Verapamil kinetics. As Verapamil is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein-bound drugs.

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 each be titrated carefully to avoid excessive cardiovascular depression. 

Clinical data and animal studies suggest that Verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). 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.

Telithromycin:Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class.

Clonidine: Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with Verapamil. Monitor heart rate in patients receiving concomitant Verapamil and clonidine. 

HMG-CoA reductase inhibitors: The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with Verapamil has been associated with reports of myopathy/rhabdomyolysis.

Co-administration of multiple doses of 10 mg of Verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. Limit the dose of simvastatin in patients on Verapamil to 10 mg daily. Limit the daily dose of lovastatin to 40 mg. Lower starting and maintenance doses of other CYP3A4 substrates (e.g., atorvastatin) may be required as Verapamil may increase the plasma concentration of these drugs.

Ivabradine: Concurrent use of verapamil increases exposure to Ivabradine and may exacerbate bradycardia and conductions disturbances.  Avoid concomitant use of Ivabradine and verapamil.

Pregnancy:  Pregnancy Category C. 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, however, 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 intravenous Verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

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

Pediatric use:  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. However, in rare instances, severe hemodynamic side effects have occurred following the intravenous administration of verapamil in 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.

The following reactions were reported with intravenous Verapamil use in controlled U.S. clinical trials involving 324 patients:

Cardiovascular: Symptomatic hypotension (1.5%); bradycardia (1.2%); severe tachycardia (1.0%). The worldwide experience in open clinical trials in more than 7,900 patients was similar.

Central nervous system effects:  Dizziness (1.2%); headache (1.2%). Although rare, cases of seizures during verapamil injection has been reported.

Gastrointestinal: Nausea (0.9%); abdominal discomfort (0.6%).

In rare cases of hypersensitivity, broncho/laryngeal spasm accompanied by itch and urticaria has been reported.

The following reactions were reported in a few patients: emotional depression, rotary nystagmus, sleepiness, vertigo, muscle fatigue, or diaphoresis.

Suggested Treatment of Acute Cardiovascular Adverse Reactions*

The frequency of these adverse reactions was quite low, and experience with their treatment has been limited.

*Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

Treatment of overdosage should be supportive and individualized. Beta-adrenergic stimulation and/or parenteral administration of calcium solutions (calcium chloride) have been effectively used in treatment of deliberate overdosage with oral Verapamil. 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 isoproterenol hydrochloride, other vasopressor agents, or cardiopulmonary resuscitation (see Suggested Treatment of Acute Cardiovascular Adverse Reactions).

For intravenous use only. VERAPAMIL SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME UNDER CONTINUOUS ECG AND BLOOD PRESSURE MONITORING. The recommended intravenous doses of Verapamil are as follows:

Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and vial seal is intact. Unused amount of solution should be discarded immediately following withdrawal of any portion of contents.

For stability reasons this product is not recommended for dilution with Sodium Lactate Injection USP in polyvinyl chloride bags. Admixing intravenous Verapamil with albumin, amphotericin B, hydralazine HCl, and trimethoprim with sulfamethoxazole should be avoided.  Verapamil will precipitate in any solution with a pH above 6.0.

All forms are individually packaged.

Store at 59° to 86°F (15° to 30°C) [See USP Controlled Room Temperature.]

The stopper in the Verapamil hydrochloride injection vial is formulated with a synthetic base-polymer and does not contain natural rubber latex.

Distributed and Manufactured By:

Exela Pharma Sciences

Lenoir, NC 28645

Revised September 2021

Rx Only                               NDC 51754-0203-1

VERAPAMIL HCl Injection, USP

5 mg/2 mL (2.5 mg/mL)

Protect from Light. For intravenous use only.

Distributed and Manufactured by:

Exela Pharma Sciences, Lenoir, NC 28645

2 mL Single-dose vial. Discard unused portion.

Rx Only                               NDC 51754-0203-2

VERAPAMIL HCl Injection, USP

5 mg/2 mL (2.5 mg/mL)

Protect from Light. For intravenous use only.

Five-2 mL Single-dose vial. Discard unused portion.

Rx Only                               NDC 51754-0203-4

VERAPAMIL HCl Injection, USP

5 mg/2 mL (2.5 mg/mL)

Protect from Light. For intravenous use only.

Twenty-Five-2 mL Single-dose vial.

Discard unused portion.

Rx Only                               NDC 51754-0205-1

VERAPAMIL HCl Injection, USP

10 mg/4 mL (2.5 mg/mL)

Protect from Light. For intravenous use only.

4 mL Single-dose vial. Discard unused portion.

Rx Only                               NDC 51754-0205-2

VERAPAMIL HCl Injection, USP

10 mg/4 mL (2.5 mg/mL)

Protect from Light. For intravenous use only.

Five-4 mL Single-dose vials.

Discard unused portion.