Verapamil Hydrochloride Injection USP (Pfizer Canada) Product Monograph

SUMMARY PRODUCT INFORMATION

INDICATIONS AND CLINICAL USE

Verapamil Hydrochloride Injection USP is indicated for life-threatening cardiac arrhythmias under the following conditions:

• 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 manoeuvres (e.g. Valsalva manoeuvre) should be attempted prior to administration of verapamil hydrochloride.
• 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).

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 and accessory bypass tract, marked hypotension, or extreme bradycardia/asystole) (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS), the use of intravenous verapamil hydrochloride should be in a treatment setting with monitoring and resuscitation facilities, including DC cardioversion capability (see OVERDOSAGE). Cardioversion has been used safely and effectively after intravenous verapamil hydrochloride.

Geriatrics (≥65 years of age):

Caution should be exercised when Verapamil Hydrochloride Injection USP is administered to elderly patients (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics (≥65 years of age)).

Pediatrics (< 18 years of age):

Caution should be used when administering Verapamil Hydrochloride Injection USP to pediatric patients.

CONTRAINDICATIONS

Verapamil Hydrochloride Injection USP is contraindicated in:

• Patients who are hypersensitive to this drug or to any ingredient in the formulation or component of the container. For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph.
• Complicated myocardial infarction (patients who have ventricular failure manifested by pulmonary congestion).
• Severe left ventricular dysfunction (see WARNINGS AND PRECAUTIONS, Cardiovascular, Heart Failure).
• Cardiogenic shock.
• Severe hypotension.
• Second- or third-degree atrioventricular (A-V) block.
• Sick sinus syndrome (see WARNINGS AND PRECAUTIONS, Cardiovascular, Conduction Disturbance).
• Marked bradycardia.
• Ventricular Tachycardia. (See WARNINGS AND PRECAUTIONS, Ventricular Tachycardia).
• Receiving intravenous beta-adrenergic blocking drugs (e.g. propanolol). Intravenous verapamil and intravenous beta adrenergic blocking drugs should not be administered in close proximity to each other (i.e. within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction (see WARNINGS AND PRECAUTIONS; DRUG INTERACTIONS Table 2).
• Patients with atrial flutter or atrial fibrillation in the presence of an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes). These patients are at risk to develop ventricular arrhythmias including ventricular fibrillation and Torsade de pointes if verapamil hydrochloride is administered (see WARNINGS AND PRECAUTIONS, Cardiovascular, Accessory Bypass Tract).
• Concomitant use of ivabradine (see DRUG INTERACTIONS).
• Patients taking flibanserin (see WARNINGS AND PRECAUTIONS, Cardiovascular, Hypotension).
• Women who are breast-feeding (see WARNINGS AND PRECAUTIONS, Special Populations, Nursing Women).

WARNINGS AND PRECAUTIONS

Verapamil Hydrochloride Injection USP should be given as a slow intravenous injection over at least a two-minute period of time and longer (at least three minutes) if the patient is 65 years of age or older (see DOSAGE AND ADMINISTRATION).

Because a small fraction (<1%) of patients treated with verapamil hydrochloride respond with life-threatening adverse responses (rapid ventricular rate in atrial flutter/fibrillation and accessory bypass tract, marked hypotension, or extreme bradycardia/asystole (see CONTRAINDICATIONS and WARNINGS AND PRECAUTIONS), the use of Verapamil Hydrochloride Injection USP should be in a treatment setting with monitoring and resuscitation facilities, including DC-cardioversion capability (see OVERDOSAGE).

General

In patients with angina or arrhythmias using antihypertensive drugs, the additional hypotensive effect of Verapamil Hydrochloride Injection USP should be taken into consideration.

Verapamil hydrochloride does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may decrease the therapeutic effect of verapamil hydrochloride.

Carcinogenesis and Mutagenesis

There was no evidence of a carcinogenic effect when verapamil hydrochloride was administered orally (diet) to male and female rats at doses up to 112.2 and 102.5 mg/kg/day, respectively, for 24 months. These doses correspond to approximately 2.3 and 2 times human exposure based on body surface area, respectively.

In vitro mutagenicity tests showed that verapamil did not have mutagenic properties in five different strains of Salmonella typhimurium, nor in studies on chromosomal aberrations and sister chromatid exchanges (SCE) in human lymphocytes, nor in the hypoxanthine guanine phosphoribosyltransferase (HGPRT)-test with V-79 Chinese hamster cells, and also not in the cell transformation assay with Syrian hamster embryo cells. In addition, verapamil did not show any SCE-inducing activity in vivo (Chinese hamster) (see TOXICOLOGY, Carcinogenicity and Mutagenicity).

Cardiovascular

Heart Failure

Because of the drug's negative inotropic effect, verapamil hydrochloride should not be used in patients with poorly compensated congestive heart failure. Continuous monitoring is mandatory when intravenous verapamil hydrochloride is used in digitalized patients.

Heart failure patients with ejection fraction higher than 40% should be treated with adequate doses of digoxin and/or diuretics before starting Verapamil Hydrochloride Injection USP treatment.

If verapamil is administered concomitantly with digoxin, reduce digoxin dosage (see DRUG INTERACTIONS, Table 2). The use of verapamil hydrochloride in the treatment of hypertension is not recommended in patients with heart failure caused by systolic dysfunction.

Hypotension

Severe hypotension has occasionally occurred following intravenous administration of the drug. On rare occasions, this has been followed by loss of consciousness. If severe hypotension develops, verapamil hydrochloride should be promptly discontinued and vasoconstrictor substances started, as described in OVERDOSAGE.

Intravenous verapamil hydrochloride often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic, but may result in dizziness. Intravenous administration of calcium chloride, or calcium gluconate prior to intravenous administration of verapamil hydrochloride may prevent this hemodynamic response (see OVERDOSAGE).

Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension.

Use of a moderate CYP3A4 inhibitor such as verapamil with flibanserin significantly increases flibanserin concentrations, which can lead to severe hypotension and syncope (see CONTRAINDICATIONS). Discontinue Verapamil Hydrochloride Injection USP at least 2 weeks prior to starting flibanserin. Do not administer Verapamil Hydrochloride Injection USP within 2 days of discontinuing flibanserin.

In patients using antihypertensive drugs, the additional hypotensive effect of verapamil hydrochloride should be taken into consideration.

Conduction Disturbance

Verapamil hydrochloride affects the A-V and sinoatrial (S-A) nodes. Verapamil hydrochloride slows conduction across the A-V node. Verapamil hydrochloride should be used with caution in the presence of first degree A-V block. Patients with first degree A-V block may progress to second or third-degree A-V block; or unifascicular, bifascicular or trifascicular bundle–branch block; they require a reduction in the dose or discontinuation of Verapamil Hydrochloride Injection USP, and the institution of appropriate therapy depending upon the patient’s clinical condition (see OVERDOSAGE).

Verapamil hydrochloride causes dose-related suppression of the S-A node and rarely may produce second or third degree A-V block, bradycardia and in extreme cases, asystole. In some patients, sinus bradycardia may occur, especially in patients with a sick sinus syndrome (S-A nodal disease), which is more common in older patients (see CONTRAINDICATIONS).

Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to A-V nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately (see ADVERSE REACTIONS and OVERDOSAGE).

Bradycardia

The total incidence of bradycardia (ventricular rate less than 50 beats/minute) was 1.4% in controlled studies.

Ventricular tachycardia

Administration of intravenous verapamil hydrochloride to patients with wide-complex ventricular tachycardia (QRS > 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pre-therapy diagnosis and differentiation from wide-complex supraventricular tachycardia (based on a 12 lead ECG) is imperative in the emergency room setting.

Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine)

Intravenous administration of verapamil hydrochloride may precipitate ventricular fibrillation. Patients with atrial flutter/fibrillation and an accessory AV pathway (e.g. Wolff-Parkinson-White or Lown-Ganong-Levine syndromes) are at risk of developing ventricular arrhythmias including ventricular fibrillation and Torsade de pointes if verapamil hydrochloride is administered. They may develop increased antegrade conduction across the aberrant pathway bypassing the AV node, producing a very rapid ventricular response after receiving verapamil hydrochloride or digitalis. This has been reported in approximately 1% of the patients treated in controlled double-blind trials. The use of verapamil hydrochloride in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC cardioversion. Cardioversion has been used safely and effectively after intravenous verapamil hydrochloride (see OVERDOSAGE).

Concomitant Use with Antiarrhythmics or Beta-Blockers

On rare occasions, the concomitant administration of intravenous beta-blockers and intravenous verapamil hydrochloride has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction. Concomitant use of verapamil hydrochloride with antiarrhythmics or beta-blockers may cause mutual potentiation of cardiovascular effects (higher-grade AV block, higher-grade lowering of heart rate, induction of heart failure and potentiated hypotension). Asymptomatic bradycardia (< 36 beats/minute) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta- adrenergic blocker) eye drops and oral verapamil hydrochloride (see DRUG INTERACTIONS, Table 2). This myocardial depressant effect (independent of changes in heart rate) can be significant in patients with impaired left ventricular performance. Accordingly, intravenous verapamil hydrochloride and intravenous beta adrenergic blocking drugs should not be administered in close proximity to each other (i.e. within a few hours).

Concomitant Use with Lidocaine

Two deaths have been reported in patients receiving both verapamil hydrochloride and lidocaine intravenously.

Concomitant Use with Procainamide

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

Concomitant Use with HMG-CoA Reductase Inhibitors (“Statins”)

Concomitant use of verapamil hydrochloride and HMG-CoA reductase inhibitors may require dosage adjustments. see (DRUG INTERACTIONS, Table 2).

Patients with Hypertrophic Cardiomyopathy

In 120 patients with hypertrophic cardiomyopathy who received oral therapy with verapamil hydrochloride at doses up to 720 mg/day, a variety of serious adverse effects were seen. Three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension, abnormally high (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see DRUG INTERACTIONS) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree A-V block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction, but in some cases, verapamil hydrochloride use had to be discontinued.

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. Similar complexes are seen during spontaneous conversion of supraventricular tachycardias after DC-cardioversion and other pharmacologic therapy. These complexes appear to have no clinical significance.

Sick Sinus Syndrome

Precaution should be taken when treating any supraventricular arrhythmia on an emergency basis as it may be caused by an undiagnosed Sick Sinus Syndrome (see CONTRAINDICATIONS).

Hepatic/Biliary/Pancreatic

Elevated Liver Enzymes

Elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. Several published cases of hepatocellular injury produced by verapamil hydrochloride have been proven by rechallenge. Clinical symptoms of malaise, fever, and/or right upper quadrant pain, in addition to elevation of serum glutamic-oxaloacetic transaminase (SGOT), serum glutamic-pyruvic transaminase (SGPT) and alkaline phosphatase have been reported. Periodic monitoring of liver function in patients receiving verapamil hydrochloride is therefore prudent.

Hepatic Insufficiency

Because verapamil hydrochloride is extensively metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function, since the elimination half-life of verapamil hydrochloride in these patients is prolonged 4-fold (from 3.7 to 14.2 hours). A decreased dosage should be used in patients with hepatic insufficiency and careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect should be carried out (see ACTION AND CLINICAL PHARMACOLOGY, Pharmacokinetics and DOSAGE AND ADMINISTRATION).

Neurologic

Neuromuscular Transmission Disorders

Due to verapamil hydrochloride’s neuromuscular blocking action, verapamil hydrochloride should be used with caution in the presence of diseases in which neuromuscular transmission is affected (myasthenia gravis, Lambert-Eaton syndrome, advanced Duchenne muscular dystrophy). It has been reported that verapamil hydrochloride decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil hydrochloride prolongs recovery from the neuromuscular blocking agent vecuronium.

The decision to administer verapamil hydrochloride should be based on the physician’s assessment of the risk and benefit to the patient. It may be necessary to decrease the dosage of verapamil hydrochloride when it is administered to patients with attenuated neuromuscular transmission. Ventilation support should be available if required (see DRUG INTERACTIONS, Drug-Drug Interactions, Use in Patients with Attenuated (Decreased) Neuromuscular Transmission).

Intravenous verapamil hydrochloride 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.

Ophthalmologic

Atypical lens changes and cataracts were observed in beagle dog studies at high doses. This has been concluded to be species-specific for the beagle dog. (These ophthalmological changes were not seen in a second study.) No similar changes have been observed in long-term prospective human ophthalmological trials.

Renal

Renal Insufficiency

About 70% of an administered dose of verapamil hydrochloride is excreted as metabolites in the urine. In one study in healthy volunteers, the total body clearance after intravenous administration of verapamil hydrochloride was 12.08 mL/min/kg, while in patients with advanced renal disease it was reduced to 5.33 mL/min/kg. This pharmacokinetic finding suggests that renal clearance of verapamil hydrochloride in patients with renal disease is decreased.

Therefore, until further data are available, Verapamil Hydrochloride Injection USP should be used with caution in patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect (see DOSAGE AND ADMINISTRATION).

Verapamil hydrochloride is not removed by hemodialysis.

Special Populations

Pregnant Women

There are no adequate and well-controlled study data in pregnant women. Verapamil hydrochloride crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil hydrochloride is not recommended for use in pregnant women unless the potential benefits outweigh potential risks to mother and fetus.

Teratology and reproduction studies have been performed in rabbits and rats with oral verapamil administered at doses up to 15 mg/kg/day and 60 mg/kg/day (human equivalent doses of 288 mg/day and 576 mg/day, respectively, assuming human body weight at 60 kg) respectively, and have revealed no evidence of teratogenicity or impaired fertility. In the rat, however, a dose of 60 mg/kg/day (human equivalent dose of 576 mg/day, similar to the maximum clinical dose of 480 mg/day) was embryocidal and retarded fetal growth and development. These effects occurred in the presence of maternal toxicity (reflected by reduced food consumption and weight gains of dams). This oral dose has also been shown to cause hypotension in rats.

Labour and Delivery

It is not known whether the use of verapamil hydrochloride during labour or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labour or increases the need for forceps delivery or other obstetric intervention.

Nursing Women

Verapamil hydrochloride is excreted in human breast milk. Because of the potential for adverse reactions in nursing infants from verapamil hydrochloride, nursing should be discontinued while Verapamil hydrochloride is administered.

Pediatrics (< 18 years of age)

Use in Children

Controlled studies with verapamil hydrochloride have not been conducted in pediatric patients. However, uncontrolled experience in more than 250 children (about 50% under 12 months of age and about 25% newborn) indicates that the results of treatment are similar to those in adults. However, in rare instances, severe hemodynamic side effects, some of them fatal, have occurred following the intravenous administration of verapamil hydrochloride in neonates and infants. Caution should therefore be used when administering verapamil hydrochloride to this group of pediatric patients.

Geriatrics (<65 years of age)

Caution should be exercised when verapamil hydrochloride is administered to elderly patients (≥65 years) especially those prone to developing hypotension or those with a history of cerebrovascular insufficiency (see DOSAGE AND ADMINISTRATION). The incidence of adverse reactions is approximately 4% higher in the elderly. The adverse reactions occurring more frequently include dizziness and constipation. Serious adverse events associated with heart block have occurred in the elderly.

Monitoring and Laboratory Tests

Patients should be monitored by measuring the blood pressure response.

Concomitant Use with Beta-Blockers

The use of intravenous verapamil hydrochloride with beta-blockers and cardiac depressant drugs can produce a reduction of myocardial contractility. This myocardial depressant effect (independent of changes in heart rate) can be significant in patients with impaired left ventricular performance.

On rare occasions the concomitant administration of intravenous beta-blockers and intravenous verapamil hydrochloride has resulted in severe adverse effects, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction (see CONTRAINDICATIONS). Accordingly, intravenous verapamil hydrochloride and intravenous beta adrenergic blocking drugs should not be administered in close proximity to each other (i.e. within a few hours).

Elevated Liver Enzymes

Periodic monitoring of liver function in patients receiving verapamil hydrochloride is prudent.

Hepatic Insufficiency

Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect should be carried out.

Renal Insufficiency

Patients with renal insufficiency should be carefully monitored for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effect.

ADVERSE REACTIONS

Adverse Drug Reaction Overview

In 4,826 patients treated with verapamil hydrochloride immediate release tablets for arrhythmias, angina or hypertension, the overall adverse reaction rate in these patients was 37.1% and the dropout rate was 10.2%. The majority of these patients were seriously ill and treated under emergency drug regulations.

In controlled pivotal studies with 128 patients treated with verapamil hydrochloride sustained-release tablets for hypertension, the overall adverse reaction rate was 21.7% and the dropout rate was 3.9%.

The most common adverse reactions were: constipation (7.3%), dizziness (3.2%), and nausea (2.7%). In hypertension studies, constipation occurred in 18.5% of patients on verapamil hydrochloride immediate release tablets and 4.7% of patients on verapamil hydrochloride sustained-release tablets.

The most serious adverse reactions reported with verapamil hydrochloride are heart failure (1.8%), hypotension (2.5%), A-V block (1.2%) and rapid ventricular response (see WARNINGS AND PRECAUTIONS).

The incidence of all adverse reactions, including those seen with both the oral and intravenous use of verapamil hydrochloride, is about 10.6%, with 6.7% associated with oral administration.

Approximately 1.4% of these patients required discontinuation of the drug because of side effects. The most common adverse effect seen with oral verapamil hydrochloride is constipation, while hypotension and bradycardia are more common with its intravenous use.

In rare cases of hypersensitive patients, broncholaryngeal spasm accompanied by itch and urticaria have been reported.

Isolated cases of angioedema have been reported. Angioedema may be accompanied by breathing difficulty. One case of anaphylactic shock following intravenous verapamil hydrochloride has also been reported.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Intravenous verapamil hydrochloride:

The following adverse reactions were reported with intravenous verapamil hydrochloride use in controlled clinical trials involving 324 patients:

Cardiovascular: Symptomatic hypotension (1.5%), bradycardia (1.2%), severe tachycardia (1%). The worldwide experience in open clinical trials in more than 7900 patients was similar.

Central Nervous System: Dizziness (1.2%), headache (1.2%). Occasional cases of seizures during verapamil hydrochloride injection have been reported.

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

Respiratory: In rare cases of hypersensitive patients, broncholaryngeal spasm accompanied by itch and urticaria have been reported.

Miscellaneous: The following reactions were reported at low frequency:

Skin reactions, exanthema, urticaria, pruritus, muscular cramps, arthralgia, emotional depression, confusion, rotary nystagmus, diplopia, impaired vision, sleepiness, insomnia, muscle fatigue, diaphoresis, painful coldness and numbness in the extremities, paresthesia, hyperkinesia, impotence.

Adverse Drug Reactions Associated with the Use of Oral Verapamil

The following adverse reactions divided by body system have been reported in clinical trials or marketing experience. When incidences are shown, they are calculated based on the 4,954 (4,826 + 128) patient base.

Table 1. Adverse Reactions Reported in Clinical Trials

Less Common Clinical Trial Adverse Drug Reactions (< 1%)

The following reactions were reported in 1.0% or less of patients in clinical trials:

Isolated cases of renal failure and angioedema have been reported. Angioedema may be accompanied by breathing difficulty.

In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or flutter, ventricular rates below 50 at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients.

Abnormal Hematologic and Clinical Chemistry Findings

Hepatotoxicity with elevated enzymes (SGOT, SGPT, alkaline phosphatase) and bilirubin levels, jaundice and associated symptoms of hepatitis with cholestasis have been reported (see WARNINGS AND PRECAUTIONS). Elevated prolactin levels have also been reported.

Post-Market Adverse Drug Reactions

The following adverse events have been reported with verapamil hydrochloride from post- marketing surveillance or Phase 4 clinical trials.

¹There has been a single post-marketing report of paralysis (tetraparesis) associated with the combined use of verapamil hydrochloride and colchicine. This may have been caused by colchicine crossing the blood-brain barrier due to CYP3A4 and P-glycoprotein (P-gp) inhibition by verapamil hydrochloride. See (DRUG INTERACTIONS).

DRUG INTERACTIONS

Drug-Drug Interactions

As with all drugs, care should be exercised when treating patients with multiple medications. Verapamil hydrochloride undergoes biotransformation by the CYP3A4, CYP1A2, CYP2C8, CYP2C9 and CYP2C18 isoenzymes of the cytochrome P450 system. Verapamil hydrochloride has also been shown to be an inhibitor of CYP3A4 enzymes and P-glycoprotein (P-gp). Co-administration of verapamil hydrochloride with other drugs which follow the same route of biotransformation or are inhibitors or inducers of these enzymes may result in altered bioavailability of verapamil hydrochloride or these drugs. Co-administration of verapamil and a drug primarily metabolized by CYP3A4 or being a P-gp substrate may be associated with elevations in drug concentrations that could increase or prolong both therapeutic and adverse effects of the concomitant drug. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered verapamil hydrochloride to maintain optimum therapeutic blood levels.

The following table provides a list of potential drug interactions:

Table 2. Potential Drug Interactions Associated with Verapamil Hydrochloride

Legend: C= Case Study; CT = Clinical Trial; T = Theoretical

Use in Patients with Attenuated (Decreased) Neuromuscular Transmission

It has been reported that verapamil hydrochloride decreases neuromuscular transmission in patients with Duchenne’s muscular dystrophy, and that verapamil hydrochloride prolongs recovery from the neuromuscular blocking agent vecuronium. Accordingly, it may be necessary to decrease the dosage of verapamil hydrochloride when it is administered to patients with attenuated neuromuscular transmission (see WARNINGS AND PRECAUTIONS: Neurologic: Neuromuscular Transmission Disorders).

Drug-Food Interactions

In healthy volunteers, multiple high doses of grapefruit juice increased the AUC for R-verapamil and S-verapamil by up to 49 and 37%, respectively. The increase in Cmax for R-verapamil and S- verapamil were up to 75 and 51%, respectively. Elimination half-life and renal clearance of both S- and R-verapamil were not affected. Grapefruit juice should therefore not be ingested with verapamil.

Drug-Herb Interactions

In healthy volunteers, multiple doses of St John’s Wort decreased the AUC for R- and S-verapamil hydrochloride by 78 and 80%, respectively, with similar decreases in Cmax.

Drug-Laboratory Interactions

Interactions with laboratory tests have not been evaluated.

Drug-Lifestyle Interactions

Verapamil hydrochloride may increase blood alcohol (ethanol) concentrations and prolong its effects.

Depending on the individual response, verapamil hydrochloride may affect the ability to react to the point of impairing the ability to drive a vehicle, operate machinery or work under hazardous conditions. This applies all the more at the start of treatment, when the dose is raised, when switching from another drug and in conjunction with alcohol.

DOSAGE AND ADMINISTRATION

Verapamil Hydrochloride Injection USP should be administered as a slow intravenous injection over at least a two minute period of time (longer if the patient is 65 years of age or older). It should be administered in hospital, where coronary care facilities are available and continuous electrocardiographic and blood pressure monitoring are performed and resuscitation facilities (including D.C. cardioversion capability) is available.

Verapamil Hydrochloride Injection USP should be inspected visually for particulate matter and discolouration prior to administration. Use only if solution is clear. Any unused portion should be discarded immediately.

Admixing verapamil hydrochloride with sodium lactate in polyvinyl chloride containers, albumin, amphotericin B, hydralazine HCl, and trimethoprim with sulfamethoxazole should be avoided. Verapamil hydrochloride will precipitate in any solution with a pH above 6.

The dosage of verapamil hydrochloride should be individualized for each patient based on response and tolerance. In some cases doses smaller than those recommended appear sufficient. Injection should only be continued to the point of therapeutic effect, at which point the intravenous infusion may be terminated, i.e. before the total recommended dose has been administered. Intravenous use of verapamil hydrochloride may be accompanied by a hypotensive response which can be precipitous, by a rapid ventricular rate, extreme bradycardia or asystole.

An intravenous preparation of calcium chloride or calcium gluconate should be available in the event of any adverse hemodynamic phenomenon. Concomitant use of beta-blockers is contraindicated.

The recommended doses of Verapamil Hydrochloride Injection USP are as follows:

Adult

Initial Dose: 5 to 10 mg (0.075-0.15 mg/kg) may be given as an intravenous bolus over at least 2 minutes.

Repeat Dose: 10 mg (0.15 mg/kg) may be injected 30 minutes after the first dose, if the initial response is not adequate. An optimal interval for subsequent intravenous doses has not been determined and should be individualized for each patient.

Elderly Patients: The dose should be administered over at least three minutes to minimize the risk of untoward drug effects.

Children

Initial Dose

0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range 0.75 to 2 mg) should be administered as an intravenous bolus over at least 2 minutes under continuous ECG monitoring.

1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range 2 to 5 mg) should be administered as an intravenous bolus over at least 2 minutes. Do not exceed 5 mg.

Repeat Dose

0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range 0.75 to 2 mg) 30 minutes after the first dose if the initial response is not adequate, under continuous ECG monitoring. An optimal interval for subsequent doses has not been determined, and should be individualized for each patient.

1 to 15 years: 0.1 to 0.3 mg/kg body weight (usual single dose range 2 to 5 mg) 30 minutes after the first dose if the initial response is not adequate. An optimal interval for subsequent doses has not been determined, and should be individualized for each patient. Do not exceed 10 mg as a single dose.

Oral therapy with verapamil hydrochloride should replace intravenous therapy as soon as possible, when the physician wishes to continue treatment with verapamil hydrochloride. Duration of treatment will depend on the underlying cause and history of recurrence.

OVERDOSAGE

Symptoms

Based on reports of intentional overdosage of verapamil hydrochloride, the following symptoms have been observed: Hypotension (varying from transient to severe), bradycardia to high degree A-V block and sinus arrest, hyperglycemia, stupor and metabolic acidosis. Conduction disturbances seen included: prolongation of A-V conduction time, A-V dissociation, nodal rhythm, ventricular fibrillation and ventricular asystole. Fatalities have occurred as a result of overdose.

Treatment

Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions (calcium chloride or calcium gluconate) may increase calcium ion influx across the slow channel.

These pharmacologic interventions have been effectively used in treatment of overdosage with oral verapamil hydrochloride. Clinically significant hypotensive reactions should be treated with vasopressor agents. A-V block is treated with atropine and cardiac pacing. Asystole should be handled by the usual Advanced Cardiac Life Support measures including the use of beta- adrenergic receptor agonists (e.g., isoproterenol hydrochloride), other vasopressor agents, or cardiopulmonary resuscitation. Verapamil hydrochloride is not removed by hemodialysis.

Actual treatment and dosage should depend on the severity of the clinical situation and the judgement of the treating physician. Patients with hypertrophic cardiomyopathy treated with verapamil hydrochloride should not be administered positive inotropic agents marked by asterisks in Table 3).

Table 3. Overdosage Adverse Reactions and Recommended Treatments

* positive inotropic agent

Definition : IV = intravenous

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

Verapamil hydrochloride is a calcium ion influx inhibitor (calcium entry blocker or calcium ion antagonist) that exerts its pharmacological effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conducting and contractile myocardial cells.

Verapamil hydrochloride exerts antihypertensive effects by inducing vasodilation and reducing peripheral vascular resistance usually without reflex tachycardia. Verapamil hydrochloride does not blunt hemodynamic response to isometric or dynamic exercise.

Verapamil hydrochloride depresses A-V nodal conduction and prolongs functional refractory periods. Verapamil hydrochloride does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibres.

Verapamil hydrochloride may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory A-V pathway following administration of verapamil hydrochloride (see WARNINGS AND PRECAUTIONS, Cardiovascular, Conduction Disturbance). Verapamil hydrochloride has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis.

Verapamil hydrochloride is a potent smooth muscle relaxant with vasodilatory properties, as well as a depressant of myocardial contractility, and these effects are largely independent of autonomic influences.

Compared to baseline, verapamil hydrochloride does not affect electrolytes, glucose, and creatinine. The hypotensive effect of verapamil hydrochloride is not blunted by an increase in sodium intake.

In hypertensive normolipidemic patients, verapamil hydrochloride had no effects on plasma lipoprotein fractions.

Verapamil's antiarrhythmic effects are believed to be brought about largely by its action on sinus and atrioventricular nodes. Electrical activity in the SA and AV nodes depends, to a significant 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 nodes 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 re-entry at the AV node, verapamil can restore normal sinus rhythm in patients with paroxysmal supraventricular tachycardias (PSVT), including Wolff-Parkinson-White (W-P-W) syndrome. Verapamil has no effect on conduction across accessory bypass tracts.

Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers.

The vasodilatory effect of verapamil appears to be due to its effect on blockade of calcium channels as well as α-receptors. Verapamil does not induce peripheral arterial spasm.

Verapamil does not alter total serum calcium levels.

Pharmacodynamics

In a study in five healthy males, the S-enantiomer was found to be 8 to 20 times more active than the R-enantiomer in slowing A-V conduction. In another study using septal strips isolated from the left ventricle of five patients with mitral disease, the S-enantiomer was 8 times more potent than the R-enantiomer in reducing myocardial contractility.

Pharmacokinetics

Distribution

Verapamil is widely distributed throughout the body tissues, the volume of distribution ranging from 1.8 to 6.8 L/kg in healthy subjects. R-verapamil is 94% bound to plasma albumin, while S-verapamil is 88% bound. In addition, R-verapamil is 92% and S-verapamil 86% bound to alpha-1 acid glycoprotein.

Verapamil hydrochloride crosses the placental barrier and can be detected in umbilical vein blood at delivery. Verapamil hydrochloride is excreted in human milk.

Metabolism

In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism by the cytochrome P-450 system in the liver. The particular isoenzymes involved are CYP3A4, CYP1A2, and CYP2C family. Thirteen metabolites have been identified in urine, most in only trace amounts. The major metabolites have been identified as various N- and O-dealkylated products of verapamil. 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, which was observed in a study in dogs. The degree of biotransformation during the first pass of verapamil hydrochloride may vary according to the status of the liver in different patient populations. In patients with hepatic insufficiency, metabolism is delayed and elimination t½ prolonged up to 14 to 16 hours.

The onset of action of a single intravenous injection is usually 1-2 minutes, with peak effect occurring between 3-5 minutes and virtual dissipation of the hemodynamic effects between 10-20 minutes. Verapamil is absorbed rapidly. From a comparison of the areas under the time concentration curves of total plasma radioactivity, following oral and IV administration, as well as based on cumulative urinary excretion, absorption has been calculated at 90 to 92%. The absolute bioavailability of unchanged verapamil is about 10 to 20% because of an intense first-pass metabolism.

The elimination of unchanged substance from plasma after intravenous administration occurs with a half-life between 3.5 and 7.4 hours. Total radioactivity, however, is eliminated with a half-life of about

24 hours.

The binding of verapamil to plasma protein is about 90%. Sixty-three to 70% of a radioactive dose was eliminated in the urine after oral as well as intravenous administration, and up to 16% was excreted in the feces.

Verapamil undergoes extensive and variable hepatic metabolism by the cytochrome P450 system. The particular isoenzymes involved are CYP 3A4, CYP 1A2 and the CYP 2C family.

Excretion

Approximately 50% of an administered dose of verapamil is eliminated renally within 24 hours, 70% within five days. Up to 16% of a dose is excreted in the feces. About 3% to 4% of an administered dose is excreted renally as unchanged drug. The total clearance of verapamil is nearly as high as the hepatic blood flow, approximately 1 L/h/kg (range: 0.7-1.3 L/h/kg).

Influence of Food

Administration of verapamil hydrochloride with food results in marked prolongation of Tmax (45 to 75%) and slight decreases in Cmax (about 15%) and AUC (1 to 8%). Food thus produces a slight decrease in bioavailability (AUC), but a narrower peak-to-trough ratio.

Hemodynamics

Verapamil reduces afterload and myocardial contractility. 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.

The commonly used intravenous doses of 5 - 10 mg verapamil produce transient, usually asymptomatic, reduction in normal systemic arterial pressure, systemic vascular resistance and contractility; left ventricular filling pressure is slightly increased.

Special Populations and Conditions

Geriatrics

The pharmacokinetics of verapamil hydrochloride are significantly different in elderly (≥ 65 years), compared to younger subjects. AUCs are increased approximately 80% with verapamil hydrochloride. In the elderly, verapamil hydrochloride clearance is reduced resulting in increases in elimination t½.

Gender

The effect of gender on verapamil hydrochloride has not been investigated.

Race

The effect of different races on verapamil hydrochloride, when administered as Verapamil Hydrochloride Injection USP, has not been investigated.

Hepatic Insufficiency

The degree of biotransformation during the first pass of verapamil hydrochloride may vary according to the status of the liver in different patient populations. In patients with hepatic insufficiency, verapamil hydrochloride clearance is reduced by 30% and elimination t½ prolonged up to 14 to 16 hours (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Hepatic Insufficiency and DOSAGE AND ADMINISTRATION).

Renal Insufficiency

About 70% of an administered dose of verapamil hydrochloride is excreted as metabolites in the urine. In one study in healthy volunteers, the total body clearance after intravenous administration of verapamil hydrochloride was 12.08 mL/min/kg, while in patients with advanced renal disease it was reduced to 5.33 mL/min/kg. This pharmacokinetic finding suggests that renal clearance of verapamil hydrochloride in patients with renal disease is decreased. In two studies with oral verapamil hydrochloride, no difference in pharmacokinetics could be demonstrated (see WARNINGS AND PRECAUTIONS, Renal, Renal Insufficiency). Verapamil hydrochloride and norverapamil are not removed by hemodialysis.

Genetic Polymorphism

The effect of genetic polymorphism on verapamil hydrochloride pharmacokinetics has not been investigated.

STORAGE AND STABILITY

Store between 20 °C and 25°C. Protect from light and freezing. Retain in carton until ready for use. For single use only. Discard unused portion.

DOSAGE FORMS, COMPOSITION AND PACKAGING

Verapamil Hydrochloride Injection USP is supplied in single dose containers as follows:

• 2.5 mg/mL in 2 mL (5 mg/2 mL,) ampoules, sleeves of 10, List 4011.
• 2.5 mg/mL in 2 mL (5 mg/2 mL,) fliptop vials, cartons of 5, List 1144.

Composition:

Verapamil Hydrochloride Injection USP is a sterile, nonpyrogenic solution containing verapamil hydrochloride 2.5 mg/mL (equivalent to 2.3 mg/mL verapamil) and sodium chloride 8.5 mg/mL in water for injection. The solution contains no bacteriostat or antimicrobial agent and is intended for single use only. May contain hydrochloric acid for pH adjustment; pH 4.9 (4.0 to 6.5).

SPECIAL HANDLING INSTRUCTIONS

Any unused portion should be discarded immediately.

Verapamil Hydrochloride Injection USP should be inspected visually for particulate matter and discolouration prior to administration. Use only if solution is clear.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper Name: Verapamil Hydrochloride

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

Structural Formula:

Molecular Formula: C₂₇H₃₈N₂O₄ . HCl

Molecular Weight: 491.07

Description:

Verapamil hydrochloride occurs as a white or almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water; freely soluble in chloroform; sparingly soluble in alcohol; practically insoluble in ether.

It has a pH between 4.5 and 6.5 and a melting range between 140° and 144°C.

DETAILED PHARMACOLOGY

Animal Pharmacology

Pharmacodynamics

Verapamil hydrochloride was initially investigated in experimental animals as a smooth muscle relaxant, with vasodilator properties. Subsequent studies have demonstrated that verapamil hydrochloride has significant antiarrhythmic effects when tested in a variety of experimental arrhythmias. The mechanism of action of verapamil hydrochloride seems to be the blocking of transmembrane influx of calcium through the slow channels, without affecting to any significant degree, transmembrane influx of sodium through the fast channels. It does not directly modify calcium uptake, binding or exchange by cardiac microsomes. Its main locus of action seems to be the superficially located membrane storage sites for calcium.

In isolated cardiac tissues, at low to moderate concentrations, verapamil exerts little or no effect on action potential amplitude, but suppresses activity in the sinoatrial (S-A) and atrioventricular (A-V) nodes. Any activity within the S-A and A-V nodes seems to be particularly sensitive to the suppressant effects of verapamil because normal impulse formation in the sinus node and conduction in the A-V node appear to be maintained by operation of slow channel mechanisms. The depressant effects exerted by verapamil on A-V nodal conduction may in part explain its effectiveness in treating supraventricular tachycardia.

Verapamil has a marked negative inotropic effect on isolated cardiac muscle. In intact animals, the depressant effect on cardiac output and stroke volume is dose-dependent.

Although verapamil has local anaesthetic properties, in clinically relevant doses it does not affect the rate of either the depolarization or the repolarization phase of the cardiac action potential. Verapamil does not have beta-blocking properties, although it antagonizes beta-adrenergic influences on the heart by a functional antagonism, due to its basic pharmacodynamic properties at the level of the conduction system and the myocardium.

In animal studies, the S-enantiomer has 15 and 50 times the activity of the R-enantiomer in reducing myocardial contractility in isolated blood-perfused dog papillary muscle and isolated rabbit papillary muscle, respectively, and twice the effect in reducing peripheral resistance.

TOXICOLOGY

Acute Toxicity

Table 4. Lethal Dose 50 (LD50) (mg/kg) of Verapamil

Symptoms preceding death were similar in both sexes with marked sedation, decreased excitability, forced respirations, clonic spasms and convulsions.

Subacute Toxicity

Oral Studies

Verapamil was administered orally in doses of 12.5, 25 and 50 mg/kg per day, to rats via food for 14 weeks (29 animals/group) and to dogs for 6 days/week in capsules, for 15 to 16 weeks (4 animals/ group). Baboons received 2, 4, 8, 16, 32 and 64 mg/kg by mouth daily for 4 weeks

(2 animals/group).

In rats, a dose-related increase in heart and lung weights was found. Dogs given 25 to 50 mg/kg showed slight weight loss and a significant reduction in heart rate up to week 11, followed by a gradual return to normal. In one dog on 12.5 mg/kg, one on 25 mg/kg and in all animals on 50 mg/kg, there was emesis during the first two weeks of the study. Serum glutamic-pyruvic transaminase (SGPT) was elevated for one dog on 25 mg/kg at week 9 and for two animals on 50 mg/kg at the end of the test. Macroscopic examinations at necropsy were negative and there were no drug-attributed histological changes. The baboons showed no drug-related changes.

Intramuscular Studies

Beagle dogs were given 0, 2 and 10 mg/kg, 5 days/week for 30 days (4 animals/group). Injection sites in all animals became edematous and a dose-related reduction in heart rate was observed. At 10 mg/kg, hemoglobin and hematocrit values decreased and one animal had a raised SGPT. At necropsy, edema was noted at injection sites and higher spleen weights were recorded at the 10 mg/kg dose. One dog on this dose also showed increased inflammatory cell infiltration in the liver, with some hepatic cell degenerative changes.

Intravenous Studies

Verapamil was given to Sprague-Dawley rats at 0.2, 1.0 and 5.0 mg/kg once daily for 4 weeks (30 animals/group) and similarly to beagle dogs at 0.1, 0.4 and 1.6 mg/kg levels (6 animals/group).

At the highest dose level, all dogs showed some restlessness, salivation and laboured breathing, along with delayed A-V conduction in one-half of the animals. In 4 of 6 animals at the highest dose (1.6 mg/kg), sporadic small focal gatherings of Kupffer cells, with death of individual liver cells (necrobioses and/or necrosis of hepatocytes), were found histopathologically.

Chronic Toxicity

Oral

Rats were given verapamil at 10, 15, 25, 30, 60 and 62.5 mg/kg/day (50 animals/group) and beagle dogs at 10, 15, 25, 30, 40, 60, 62.5, 70, 81 and 85 mg/kg (6 animals/group) for 12 and 18 months. Clinical signs were observed and changes in food consumption, consistency of stools, hemograms, clinical chemistry and urinalyses performed. Blood pressure, electrocardiogram (ECG) and ophthalmoscopic examinations were done on the dogs.

In one 18-month rat study, an increase in weight of the thyroid glands in females on the 62.5 mg/kg dose was noted. In a later 12-month study, a slight reduction in weight gain was recorded.

In dogs, at doses of 60 mg/kg and greater, toxic signs such as vomiting, salivation, reversible hyperplasia of the gums, reduced food consumption, slight weight loss and a transitory, slight to moderate elevation of SGPT were noted and three of the animals died. The 40 mg/kg dose caused loss of coat colour and hair, and a delay in A-V conduction.

In another study, atypical lens changes (cataracts) were observed in eight beagles receiving toxic dose levels (62.5 and 70 mg/kg). In a later study, four beagles were given 81 mg/kg for 18 months and none developed cataracts. It was concluded that any changes caused by verapamil in lens transparency are specific to the beagle. This is supported by the absence of similar lesions in other species studied, and by the apparent lack of any impairment by verapamil of carbohydrate or energy metabolism in lenticular tissue. The water-soluble proteins of the canine lens are known to have differences from those in other species.

Mutagenicity and Carcinogenicity

Mutagenicity

In vitro mutagenicity tests showed that verapamil did not have mutagenic properties in five different strains of Salmonella typhimurium, nor in studies on chromosomal aberrations and sister chromatid exchanges (SCE) in human lymphocytes, nor in the hypoxanthine guanine phosphoribosyltransferase (HGPRT)-test with V-79 Chinese hamster cells, and also not in the cell transformation assay with Syrian hamster embryo cells. In addition, verapamil did not show any SCE-inducing activity in vivo (Chinese hamster).

Carcinogenicity

In a 24-month carcinogenicity study, verapamil hydrochloride was administered orally to 50 male and 50 female rats in the diet as actual mean doses of 9.3/9.5, 32.6/33.2, and 112.2/102.5 mg/kg/day, respectively.

Two hundred animals served as controls.

Drug-related significant reductions in body weight and mortality were seen in males and females of the high dose group.

Dose-related cardiac lesions (dilatation, atrial thrombi and myocardial metaplasia, combined with hydrothorax) were seen in the high dose group. These cardiac lesions are considered related to a chronic, exaggerated pharmacologic effect at this high dose level.

At the end of the study, all rats were examined histopathologically with regards to tumorigenesis. All non-neoplastic and neoplastic lesions were considered to reflect the spectrum of spontaneous lesions commonly encountered in rats of this age and strain. As compared to the controls, the type and incidence of these lesions were not increased in treated rats.

Irritation

Two concentrations of verapamil, 10 mg/mL in a 1 mL dose and 50 mg/mL in 0.25, 0.5 and 1 mL dose were injected intramuscularly into 5 albino rabbits, with each animal receiving the 4 doses once. Gross signs of irritation consisted mainly of congestion at the injection sites, with no evidence of necrosis or other degenerative changes.

In another study, verapamil was examined in mongrel dogs for local tolerance after single intravenous, intramuscular, paravenous and intra-arterial administration of about 5 mg/animal. Sites of injection were checked daily for manifestations of inflammation and sensitivity to pressure. Later, several tissue specimens were taken from the respective injection sites and examined histologically. The intravenous injection of verapamil caused no irritation. After intramuscular, paravenous and intra-arterial administration changes observed were mild inflammation or slight degenerative alterations in muscle cells. These were reversible.

Reproduction and Teratology

Studies were carried out in rats and rabbits with verapamil given in food and/or by gastric tube. These studies included fertility and general reproduction performance in rats, teratogenicity studies in rats and rabbits and peri- and post-natal studies in rats. Rats were given 2.5, 12.5, 25 and 100 mg/kg body weight, by gastric tube and 1.3, 1.6, 5.2, 7.5, 13.3, 16 and 55 mg/kg body weight in food. In another teratogenicity study, rats were given 5, 10 and 20 mg/kg body weight by gavage three times daily at an interval of about 4.5 hours. Rabbits were given 5 and 15 mg/kg body weight by gastric tube.

There was no evidence of teratogenicity in either species and no embryotoxic effects observed in the rats dosed via food, or with doses up to 12.5 mg/kg body weight given by gastric tube, or with doses up to 10 mg/kg three times a day. The single daily dose of 25 mg/kg body weight or more, caused a higher resorption rate in the rat. The dose of 20 mg/kg three times a day 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 was no difference in resorption rates observed in the rabbit and no effect on peri- and post-natal development or fertility in the rat.

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