Isoptin IV (Verapamil HCl)

ISOPTIN® I.V.

Knoll

Verapamil HCl

Antiarrhythmic

Action And Clinical Pharmacology: Mode of Action: The mechanism of action of verapamil is believed to be related to its specific cellular action of selectively inhibiting transmembrane influx of calcium in cardiac muscle, coronary and systemic arteries and in cells of the intracardiac conduction system.

Verapamil blocks the transmembrane influx of calcium ion through the slow channel (calcium ion antagonism) without affecting to any significant degree the transmembrane influx of sodium through the fast channel. This results in a reduction of free calcium ions available within the cells of the above tissues.

Verapamil’s antiarrhythmic effects are believed to be brought about largely by its action on the sinus and atrioventricular nodes. Electrical activity in the SA and AV nodes depends, to a large extent, 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.

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.

By interrupting re-entry 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.

It has no effect on conduction across accessory bypass tracts.

The vasodilatory effect of verapamil appears to be due to its effect on blockade of calcium channels as well as a-receptors. 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.

Pharmacokinetics: The onset of action of a single i.v. injection is usually 1 to 2 minutes, with peak effect occurring between 3 to 5 minutes and virtual dissipation of the hemodynamic effects between 10 to 20 minutes.

Verapamil is absorbed rapidly. From a comparison of the areas under the time concentration curves of total plasma radioactivity, following oral and i.v. 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 the plasma after i.v. 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.

Elimination half-life may be prolonged in the elderly.

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 i.v. administration and up to 16% was excreted in the feces.

In healthy men, orally administered verapamil undergoes extensive metabolism in the liver, 12 metabolites having been identified, most in only trace amounts. The chief metabolites are the primary and secondary amines and norverapamil.

Verapamil is metabolized through the cytochrome P450 system. The particular isoenzymes involved are CYP 3A4, CYP 1A2, and the CYP 2C family.

Hemodynamics: Verapamil reduces afterload and myocardial contractility. The commonly used i.v. dose of 5 to 10 mg produces 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.

Indications And Clinical Uses: 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 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).

Contra-Indications: Acute myocardial infarction.

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

Cardiogenic shock or severe hypotension.

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).

Concomitant use of injectable verapamil with beta-blockers and cardiac depressant drugs.

The use of i.v. verapamil with these drugs can produce a reduction in 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 i.v. beta-blockers and i.v. verapamil has resulted in serious adverse reactions, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction. Accordingly, i.v. verapamil and i.v. beta adrenergic blocking drugs should not be administered in close proximity to each other (i.e., within a few hours).

Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., 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 i.v. verapamil to patients with wide-complex ventricular tachycardia (QRS ³0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide complex supraventricular tachycardia (based on a 12 lead ECG) is imperative in the emergency room setting.

Hypersensitivity to the drug.

Manufacturers’ Warnings In Clinical States: Verapamil should be given as a slow i.v. injection over at least a 2 minute period of time (see Dosage).

Heart Failure: Because of the drug’s negative inotropic effect, verapamil should not be used in patients with poorly compensated congestive heart failure, unless the failure is complicated by or caused by an arrhythmia. If verapamil is used in such patients, they must be digitalized prior to treatment. Continuous monitoring is mandatory when i.v. verapamil is used in digitalized patients. It has been reported that digoxin plasma levels may increase with chronic oral administration (see Warnings, Concomitant Antiarrhythmic Therapy).

Hypotension: Severe hypotension has occasionally occurred following i.v. administration of the drug. On rare occasions, this has been followed by loss of consciousness. If severe hypotension develops, verapamil should be promptly discontinued and vasoconstrictor substances used as described in Overdose: Symptoms and Treatment.

I.V. verapamil often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic, but may result in dizziness. Administration of i.v. calcium chloride or calcium gluconate prior to i.v. administration of verapamil may prevent this hemodynamic response.

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

Ventricular Fibrillation: I.V. administration may precipitate ventricular fibrillation. Patients with atrial flutter/fibrillation and an accessory AV pathway (e.g. Wolff-Parkinson-White or Lown-Ganong-Levine syndromes) may develop increased antegrade conduction across the aberrant pathway bypassing the AV node, producing a very rapid ventricular response after receiving verapamil (or digitalis). This has been reported in 1% of the patients treated in controlled double blind trials. Treatment is usually DC cardioversion. Cardioversion has been used safely and effectively after i.v. verapamil (see Overdose: Symptoms and Treatment).

Bradycardia/Asystole: Verapamil slows conduction across the AV node 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 (see Contraindications).

A total incidence of bradycardia (ventricular rate less than 60 beats/min) was 1.2% in controlled i.v. and oral 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 Overdose: Symptoms and Treatment).

Impaired Hepatic or Renal Function: Because verapamil is extensively metabolized in the liver, decreased dosage should be used in patients with hepatic insufficiency.

About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Therefore, verapamil should be used cautiously in patients with impaired renal function.

Patients with impaired hepatic and/or renal function should be monitored carefully for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects.

Verapamil cannot be removed by hemodialysis.

Duchenne’s Muscular Dystrophy: I.V. verapamil can precipitate respiratory muscle failure in these patients and should, therefore, be used with caution.

Increased Intracranial Pressure: I.V. verapamil 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.

Concomitant Antiarrhythmic Therapy: Digitalis Glycosides: I.V. 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.

Verapamil produces a significant increase in serum digoxin concentration. This effect is dose dependent and occurs with continued administration of verapamil. This phenomenon has been at least partially explained by reduced renal excretion of digoxin. As digoxin toxicity may therefore occur, the dose of digoxin may need downward adjustment in patients who are receiving verapamil concomitantly.

Lidocaine: Two deaths have been reported in patients receiving both verapamil and lidocaine i.v.

Beta-adrenergic Blockers: On rare occasions, the concomitant administration of verapamil with beta-blockers has resulted in severe adverse effects, especially in patients with severe cardiomyopathy, congestive heart failure or recent myocardial infarction (see Contraindications).

Verapamil gives no protection against the dangers of abrupt beta-blocker withdrawal; any such withdrawal should be by gradual reduction of the dose of beta-blocker.

Disopyramide: Until data on possible interactions between disopyramide and verapamil are available, disopyramide should not be administered within 48 hours before or 24 hours after verapamil.

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

Quinidine: I.V. verapamil has been administered to a small number of patients receiving oral quinidine without the occurrence of serious adverse effects. However, several 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 a-adrenergic receptors. Caution should therefore be used when employing this combination of drugs.

Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in an additive negative inotropic effect and prolongation of atrioventricular conduction.

Precautions: 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 and Warnings).

Heart Block: 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 Overdose: Symptoms and Treatment).

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. 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.

Pregnancy: Teratology and reproduction studies in animals have not revealed any evidence of impaired fertility or teratogenic potential. There are no studies in pregnant women. In all patients of childbearing potential, anticipated benefits must be weighed against possible hazards.

Preliminary studies have shown that unchanged drug crosses the placental barrier.

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 i.v. verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Lactation: 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 adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Children: Controlled studies with verapamil have not been conducted in pediatric patients, but uncontrolled experience with i.v. 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 i.v. administration of verapamil in neonates and infants. Caution should therefore be used when administering verapamil to this group of pediatric patients.

Drug Interactions: As with all drugs, care should be exercised when treating patients with multiple medications. Calcium channel blockers undergo biotransformation by the cytochrome P450 system. Coadministration of verapamil with other drugs which follow the same route of biotransformation may result in altered bioavailability of verapamil or these drugs. 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 to maintain optimum therapeutic blood levels.

Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, terfenadine, warfarin.

Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.

Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, theophylline.

Alpha-adrenergic Blockers: Concomitant use of verapamil with a-adrenergic blockers may result in an exaggerated hypotensive response.

Antineoplastic Agents: Verapamil inhibits P-glycoprotein mediated transport of antineoplastic agents out of tumor cells, resulting in their decreased metabolic clearance. Dosage adjustments of antineoplastic agents should be considered when verapamil is administered concomitantly.

ASA: Potential adverse reactions in terms of bleeding due to synergistic antiplatelet effects of the two agents should be taken into consideration in patients taking verapamil and ASA concomitantly.

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

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.

Concomitant Antiarrhythmic Therapy: See Warnings.

Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine.

Dantrolene: Two animal studies suggest concomitant i.v. 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 i.v. dantrolene.

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.

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.

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.

Phenobarbital: Phenobarbital therapy may increase verapamil clearance.

Plasma Bound Drugs: As verapamil is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein bound drugs.

Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability.

Adverse Reactions: The incidence of all adverse reactions, including those seen with both the oral and i.v. use of verapamil 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 is constipation, while hypotension and bradycardia are most common with its i.v. 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 i.v. verapamil has also been reported.

The following adverse reactions were reported with i.v. verapamil 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 7 900 patients was similar.

CNS: dizziness (1.2%); headache (1.2%). Occasional cases of seizures during verapamil 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.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: Hypotension occurs, varying from transient to severe. Conduction disturbances seen included: prolongation of AV conduction time, AV dissociation, nodal rhythm, ventricular fibrillation and ventricular asystole.

Treatment of overdosage should be supportive and individualized. Beta-adrenergic stimulation and/or parenteral administration of calcium solutions (calcium chloride or calcium gluconate) may increase calcium ion flux across the slow channel. These pharmacologic interventions have been effectively used in treatment of deliberate overdosage with oral verapamil.

Clinically significant hypotensive reactions should be treated with vasopressor agents.

AV block should be treated with atropine and cardiac pacing. Asystole should be handled by the usual measures including isoproterenol hydrochloride, other vasopressor agents, or cardiopulmonary resuscitation.

Verapamil cannot be removed by hemodialysis.

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

Dosage And Administration: Verapamil should be given as a slow i.v. injection over at least a 2 minute period of time, in hospital, where coronary care facilities are available and continuous ECG and blood pressure monitoring are performed.

Verapamil injection should be inspected visually for particulate matter and discoloration prior to administration.

Admixing 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.

The dosage regimen for verapamil should be individualized for each patient based on response and tolerance. Injections should be continued only to the point where therapeutic effect has been achieved, at which point the i.v. infusion may be terminated, i.e., before the total recommended dose has been administered. Its i.v. use may be accompanied by a hypotensive response which can be precipitous, by a rapid ventricular rate, extreme bradycardia, or asystole.

An i.v. 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 i.v. doses are as follows: Adults: Initial dose: 5 to 10 mg (0.075 to 0.15 mg/kg body weight) given as an i.v. bolus over at least 2 minutes.

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

Older Patients: The dose should be administered over at least 3 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 i.v. 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 i.v. 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 treatment should replace i.v. therapy as soon as possible, when the physician wishes to continue treatment with verapamil. Duration of treatment will depend on the underlying cause and history of recurrence.

Stability: Isoptin injection is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in the following large volume parenteral solutions in glass, polyvinyl chloride and polyolefin containers at a nominal concentration of 40 mg/L: 5% Dextrose, 0.9% Sodium Chloride, Ringer’s, Ringer’s Lactate and combinations thereof.

Availability And Storage: Each mL of sterile, clear, colorless aqueous solution, contains: verapamil HCl 2.5 mg and sodium chloride 8.5 mg. pH adjusted with hydrochloric acid and/or sodium hydroxide. Preservative-free. Clear glass ampuls of 2 mL. Clear glass, single use vials of 2 and 4 mL. Packages of 10. Store between 15 and 30°C. Do not freeze. Protect from light. Do not use beyond the expiry date indicated on the label.

ISOPTIN® I.V. Knoll Verapamil HCl Antiarrhythmic

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