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Uses

Verapamil is used in the management of supraventricular tachycardias (SVTs). The drug also is used for the management of Prinzmetal variant angina and unstable and chronic stable angina pectoris, and for the management of hypertension.

Supraventricular Arrhythmias

Verapamil is used for rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT), including tachycardia associated with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome; the drug also is used for control of rapid ventricular rate in nonpreexcited atrial flutter or fibrillation. The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guideline for the management of adult patients with supraventricular tachycardia recommends the use of verapamil in the treatment of various SVTs (e.g., atrial flutter, junctional tachycardia, focal atrial tachycardia, atrioventricular nodal reentrant tachycardia [AVNRT]); in general, IV verapamil is recommended for acute treatment, while oral verapamil is recommended for ongoing management of these arrhythmias. Vagal maneuvers and/or IV adenosine are considered first-line interventions for the acute treatment of patients with SVT and should be attempted prior to other therapies when clinically indicated; if such measures are ineffective or not feasible, a nondihydropyridine calcium-channel blocker (i.e., verapamil or diltiazem) may be considered. Verapamil should only be used in hemodynamically stable patients who do not have impaired ventricular function.

Paroxysmal Supraventricular Tachycardia

IV verapamil is used for rapid conversion of PSVT that is uncontrolled or unconverted by vagal maneuvers and adenosine, including atrioventricular nodal reentrant tachycardias and PSVT associated with accessory bypass tracts (e.g., Wolff-Parkinson-White or Lown-Ganong-Levine syndrome). In 60-100% of patients with PSVT, rapid (usually within 10 minutes after administration) conversion to sinus rhythm is achieved with IV verapamil.

Verapamil is used orally to prevent recurrent PSVT and is considered a drug of choice for this arrhythmia. The drug appears to be more effective in preventing PSVT associated with AV nodal reentry than that associated with a concealed accessory pathway.

Atrial Fibrillation and Flutter

Nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) are recommended as one of several drug therapy options for ventricular rate control in patients with nonpreexcited atrial fibrillation or flutter. Management of atrial fibrillation or flutter depends on the clinical situation and the patient's condition. For acute treatment of atrial fibrillation, IV verapamil may be used to temporarily control rapid ventricular rate, usually decreasing heart rate by at least 20%. Cardioversion is indicated, however, in hemodynamically unstable patients. Verapamil should not be used when atrial flutter or fibrillation (especially when preexcited ventricular complexes are present) is associated with an accessory bypass tract (e.g., Wolff-Parkinson-White or Lown-Ganong-Levine syndrome), since ventricular tachyarrythmias, including ventricular fibrillation, and cardiac arrest may be precipitated.(See Cautions: Cardiovascular Effects.) Although approximately 70% of patients with atrial flutter and/or fibrillation respond to IV verapamil with a reduction in ventricular rate, the drug alone rarely converts atrial flutter or fibrillation to normal sinus rhythm. Conversion is more likely to occur in atrial flutter or fibrillation that is of recent onset and/or associated with only mild or moderate left-atrial enlargement.

Because of the potential negative inotropic effect of verapamil and recent concerns about the use of calcium-channel blockers in acute myocardial infarction (see Cautions: Precautions and Contraindications), these drugs are not recommended as first-line agents following an acute myocardial infarction despite their efficacy in slowing heart rate, especially in patients already receiving a β-adrenergic blocking agent. Generally, calcium-channel blockers (i.e., verapamil or diltiazem) are reserved for the management of atrial fibrillation associated with acute myocardial infarction when β-blockers are contraindicated or ineffective.(See Uses: Acute Myocardial Infarction.)

Oral verapamil is used in conjunction with a cardiac glycoside (e.g., digoxin) to control ventricular rate at rest and during stress in patients with chronic atrial fibrillation and/or flutter. Verapamil has also been used alone and in combination with quinidine to control ventricular rate in these patients. The drug should not be used when these arrhythmias are associated with an accessory bypass tract. Unlike cardiac glycosides, verapamil may be particularly useful in controlling tachycardia induced by exercise and stress. Verapamil reduces heart rate at rest (e.g., by 15-30%) and increases exercise capacity in patients with chronic atrial fibrillation and/or flutter, and has been effective in patients who did not respond adequately to a cardiac glycoside alone. Improvement in maximal exercise capacity occurs with a concomitant decrease in heart rate, blood pressure, and double product (heart rate times systolic blood pressure) at maximal exertion during verapamil therapy. Combined therapy with verapamil and a cardiac glycoside appears to be somewhat more effective than verapamil or a cardiac glycoside alone. Cardioversion has been used safely and effectively following IV or oral verapamil administration.

Although controlled studies have not been conducted to date, IV verapamil also has been used successfully in the management of PSVT and atrial fibrillation or flutter in neonates and children. However, most experts state that verapamil should not be used in infants because it may cause refractory hypotension and cardiac arrest and should be used with caution in children because it may cause hypotension and myocardial depression.(see Cautions: Pediatric Precautions.)

Atrial Tachycardia

IV verapamil may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia (i.e., regular SVT arising from a localized atrial site), and oral verapamil may be used for ongoing management.

While evidence is more limited, IV verapamil also has been used in patients with multifocal atrial tachycardia (i.e., rapid, irregular rhythm with at least 3 distinct P-wave morphologies) to control ventricular rate and convert to normal sinus rhythm. However, such arrhythmia is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic therapy. Antiarrhythmic drug therapy usually is reserved for patients who do not respond to initial attempts at correcting or managing potential precipitating factors (e.g., exacerbation of chronic obstructive pulmonary disease or congestive heart failure, electrolyte and/or ventilatory disturbances, infection, theophylline toxicity). Therapy with verapamil has been associated with slowing of atrial and ventricular rates and conversion to sinus rhythm in some patients with this arrhythmia. Therefore, some clinicians suggest that IV verapamil may be useful for the acute treatment of patients with multifocal atrial tachycardia who do not have ventricular dysfunction, sinus node dysfunction, or AV block. Verapamil also may be useful orally for chronic suppression of recurrent symptomatic multifocal atrial tachycardia.

Junctional Tachycardia

Verapamil may be used for the treatment of junctional tachycardia (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia. β-Adrenergic blocking agents generally are used for acute termination and/or ongoing management of junctional tachycardia; limited evidence suggest there may be a role for verapamil when β-blocking agents (particularly propranolol) are ineffective.

Angina

Oral calcium-channel blocking agents are considered the drugs of choice for the management of Prinzmetal variant angina. A nondihydropyridine calcium-channel blocker (e.g., diltiazem, verapamil) also has been recommended in patients with unstable angina who have continuing or ongoing ischemia when therapy with β-blocking agents and nitrates is inadequate, not tolerated, or contraindicated and when severe left ventricular dysfunction, pulmonary edema, or other contraindications are not present. In the management of unstable or chronic stable angina pectoris, verapamil appears to be as effective as β-adrenergic blocking agents (e.g., propranolol) and/or oral nitrates. In unstable or chronic stable angina pectoris, verapamil may reduce the frequency of attacks, allow a decrease in sublingual nitroglycerin dosage, and increase the patient's exercise tolerance. Although evidence suggests that concurrent use of verapamil and a β-adrenergic blocking agent may be beneficial in patients with unstable or chronic stable angina pectoris, additional study is needed to determine the safety and efficacy of concomitant therapy, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. (See Drug Interactions: β-Adrenergic Blocking Agents.) Although concomitant therapy with verapamil, nitroglycerin, and a β-adrenergic blocking agent may be beneficial in some patients, the safety and/or efficacy of such therapy have not been fully determined.

Hypertension

Verapamil is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.

Calcium-channel blocking agents (e.g., verapamil) are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.

Calcium-channel blockers may be particularly useful in the management of hypertension in black patients; these patients tend to have greater blood pressure response to calcium-channel blockers and thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists). Use of a calcium-channel blocker also may be beneficial in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina) and in geriatric patients, including those with isolated systolic hypertension. In addition, nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) may be beneficial in hypertensive patients with coexisting atrial fibrillation and a rapid ventricular rate.

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk for coronary heart disease. Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed. Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure. The ALLHAT investigators suggested that the favorable cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.

For additional information on the role of calcium-channel blockers in the management of hypertension, . For information on overall principles and expert recommendations for treatment of hypertension,

Hypertrophic Cardiomyopathy

Verapamil has been used as adjunctive therapy in the management of hypertrophic cardiomyopathy. The drug is used to relieve cardiac manifestations (e.g., angina, dyspnea) and improve exercise capacity and quality of life associated with cardiomyopathy-induced outflow tract obstruction and also may alleviate and suppress concomitant supraventricular tachyarrhythmias. Verapamil therapy also has produced clinical improvement in patients without evidence of outflow obstruction. The drug can reduce the outflow tract gradient in patients with obstruction and enhance left ventricular diastolic filling (e.g., rate) and relaxation; the drug also appears to reduce regional systolic and diastolic asynchrony. In addition, limited evidence suggests that verapamil may limit the extent of ischemic myocardial changes in some patients with hypertrophic cardiomyopathy; however, the drug may not alter the underlying hypertrophic process, which apparently can progress slowly despite clinical and cardiac functional improvements induced by the drug and evidence of an increase in the number of calcium-channel blocking agent receptors (1,4-dihydropyridine receptors) in the myocardium of patients with this condition.

While clinical improvement frequently occurs in patients with hypertrophic cardiomyopathy treated with verapamil, improvement in the extent of hypertrophy as evidenced by changes in intraventricular septum (IVS) and left ventricular posterior wall (LVPW) thickness and in left ventricular diameters appears to occur only occasionally. In one study, there was no change in these parameters overall in patients receiving verapamil, although 13% of these patients exhibited decreases in IVS and/or LVPW thickness. The clinical importance of such changes is not known, but some evidence suggests that decreases in LVPW thickness in patients with hypertrophic cardiomyopathy actually may result in left ventricular systolic dysfunction.

Despite evidence of a lack of substantial effect on the underlying hypertrophic process, functional cardiac changes induced by verapamil, particularly those involving left ventricular diastolic filling, relaxation, and asynchrony, can result in decreased ischemic manifestations, including symptomatic improvement and increased exercise tolerance. While the role of chronic drug therapy in asymptomatic patients with hypertrophic cardiomyopathy remains controversial, verapamil has improved reversible perfusion defects and exercise capacity in such patients, and some clinicians suggest that such therapy can be considered for relatively young patients with a family history of premature sudden death and those with marked ventricular hypertrophy or marked subaortic stenosis.

Verapamil appears to be more effective than propranolol as adjunctive therapy in the management of hypertrophic cardiomyopathy and often is effective and can delay the need for surgery in patients who fail to respond to β-adrenergic blocker therapy. In one study, most such patients improved clinically following discontinuance of propranolol and initiation of verapamil, and in many of those in whom symptoms were considered severe enough to warrant surgery, improvement was sufficient to delay the need for surgery. In another comparative study, clinical and hemodynamic improvement was greater with verapamil than with propranolol. However, because response to drug therapy in patients with hypertrophic cardiomyopathy is variable, probably secondary to the complexity and relative contribution of various underlying pathophysiologic mechanisms in this condition, such therapy should be individualized.

Additional study and experience are necessary to determine whether the beneficial effects of verapamil in hypertrophic cardiomyopathy persist during long-term therapy. Some evidence suggests that potential benefits may diminish with time. In addition, verapamil should be used for hypertrophic cardiomyopathy with extreme caution and only when other alternatives are not considered suitable in patients with elevated pulmonary venous pressures (particularly when combined with a baseline outflow obstruction), paroxysmal nocturnal dyspnea or orthopnea, or clinically important SA nodal or AV junctional conduction abnormalities (unless a functional artificial ventricular pacemaker is in place).

Acute Myocardial Infarction

Calcium-channel blocking agents have not proved beneficial in the early treatment or secondary prevention of acute myocardial infarction, and the possibility that they may be harmful has been raised.(See Cautions: Precautions and Contraindications.) However, verapamil or diltiazem generally can be used after an acute myocardial infarction when β-adrenergic blocking agents are ineffective or contraindicated for the relief of ongoing ischemia or to control rapid ventricular response with atrial fibrillation, but only in patients in whom there is no evidence of congestive heart failure, left-ventricular dysfunction, or AV block and only after weighing carefully the potential benefits versus risks, particularly negative inotropic effects and recent concerns about short-acting formulations of the drugs. In patients with first non-Q-wave infarction or first anterior infarction without left-ventricular dysfunction or pulmonary congestion, verapamil or diltiazem may reduce the incidence of reinfarction, but their benefit beyond that of β-adrenergic agents and aspirin is unclear. Although a clear mortality benefit has not been demonstrated, subgroup analysis of clinical trials indicates that immediate-release verapamil initiated several days after acute myocardial infarction in patients who were not candidates for β-blocker therapy may be beneficial in reducing the incidence of combined endpoint of reinfarction and death, provided that left-ventricular function is well preserved and there is no clinical evidence of heart failure. In one large study in patients younger than 75 years of age, verapamil initiated within 2 weeks after acute myocardial infarction decreased major endpoints (death or reinfarction) over 18 months. Therefore, if β-adrenergic blocking agents are contraindicated or poorly tolerated, verapamil or diltiazem can be considered for secondary prevention as an alternative to β-blockers in patients with preserved left ventricular function. Verapamil is detrimental to patients with heart failure or bradyarrhythmias during the initial 24-48 hours after infarction. The drug is contraindicated in patients with acute myocardial infarction that is accompanied by left-ventricular dysfunction or congestive heart failure.(See Cautions: Precautions and Contraindications.)

Other Uses

Verapamil has been used orally with some success in a limited number of patients for the management of manic manifestations of bipolar disorder, but additional study is needed.

Dosage and Administration

Administration

Verapamil hydrochloride is administered by direct IV injection or orally. The drug has also been administered by IV infusion, but safety and efficacy of this method of administration have not been established.

For IV administration, verapamil hydrochloride is given slowly under continuous ECG and blood pressure monitoring as a direct injection over a period of not less than 2 minutes or, in geriatric patients, of not less than 3 minutes. Solutions of the drug should be inspected visually for particulate matter prior to IV administration whenever solution and container permit.

The manufacturers recommend that extended-release tablets of the drug be administered with food, since smaller differences between peak and trough serum verapamil concentrations occur with such administration. Oral bioavailability of the extended-release tablets is not affected by halving the tablets. Conventional tablets, extended-release capsules, extended-release core tablets, and controlled extended-release capsules can be administered without regard to food. Verapamil hydrochloride extended-release core tablets (Covera-HS) should be swallowed intact and should not be chewed, broken, or crushed.

The commercially available extended-release capsules containing pellets of verapamil hydrochloride (Verelan) may be swallowed intact and should not be chewed. Alternatively, the entire contents of a capsule may be sprinkled on a small amount of applesauce immediately prior to administration; patients should drink a glass of cool water to ensure complete swallowing the pellets. In addition, the applesauce should not be hot, and should be soft enough to be swallowed without chewing. The mixture of applesauce and pellets should not be stored for future use; subdividing the contents of a capsule is not recommended. Studies to establish bioequivalence of controlled extended-release pellets (Verelan PM) sprinkled on applesauce have not been conducted to date.

Dosage

Potency of verapamil hydrochloride preparations is expressed in terms of the hydrochloride.(See Chemistry and Stability: Chemistry.)

Dosage of verapamil hydrochloride must be carefully titrated according to individual requirements and response. Safety and efficacy of adult oral verapamil hydrochloride dosages exceeding 480 mg daily have not been established.

Supraventricular Arrhythmias

Parenteral Dosage

For the management of supraventricular tachycardia (SVT) in adults, the usual initial IV dose of verapamil hydrochloride recommended by the manufacturer is 5-10 mg (0.075-0.15 mg/kg). Slower infusion rates (over at least 3 minutes) should be used in geriatric patients in order to minimize the risk of adverse effects. If the patient tolerates but does not respond adequately to the initial IV dose, a second IV dose of 10 mg (0.15 mg/kg) may be given 30 minutes after the initial dose.

For the management of SVT in children younger than 1 year of age, the usual initial IV dose of verapamil hydrochloride recommended by the manufacturer is 0.75-2 mg (0.1-0.2 mg/kg) administered over at least 2 minutes under continuous ECG monitoring. In children 1-15 years of age, the usual initial IV dose is 2-5 mg (0.1-0.3 mg/kg), but should not exceed 5 mg. The initial pediatric dose may be repeated once after 30 minutes if an adequate response is not achieved. In children 1-15 years of age, the repeat dose should not exceed 10 mg. Because severe adverse cardiovascular effects have been associated with IV administration of verapamil, most experts state that IV verapamil should not be used in infants and should be used with caution in children.(See Cautions: Pediatric Precautions.)

Oral Dosage

The usual oral dosage of verapamil hydrochloride for the prevention of recurrent paroxysmal supraventricular tachycardia (PSVT) in adults is 240-480 mg daily given in 3 or 4 divided doses as conventional tablets. To control ventricular rate in digitalized adults with chronic atrial flutter and/or fibrillation, the usual adult oral dosage of verapamil hydrochloride is 240-320 mg daily given in 3 or 4 divided doses as conventional tablets. Maximum antiarrhythmic effects are generally apparent within 48 hours after initiating a given verapamil dosage.

Angina

For the management of Prinzmetal variant angina or unstable or chronic stable angina pectoris, the usual initial adult oral dosage of verapamil hydrochloride is 80 mg every 6-8 hours. Dosage of the drug may be gradually increased by 80-mg increments at weekly intervals or, in patients with unstable angina, at daily intervals until optimum control of angina is obtained. Lower dosages (e.g., 40 mg every 8 hours) may be necessary in geriatric or other patients who may have an increased response to the drug. Although maximum pharmacologic effects may occur 24-48 hours after dosage adjustment, maximum pharmacologic and therapeutic response may be delayed since the half-life of the drug increases during this period of time after dosage adjustment. The adult oral maintenance dosage ranges from 240-480 mg daily but usually is 320-480 mg daily, given in 3 or 4 divided doses.

Alternatively for the management of angina, the extended-release core tablets (Covera-HS) may be used. The usual initial dosage of the drug as extended-release core tablets is 180 mg at bedtime. If adequate response does not occur, dosage may be increased to 240 mg daily, and subsequently dosage may be increased by 120-mg increments to 480 mg daily at bedtime.

Hypertension

For the management of hypertension in adults, verapamil hydrochloride extended-release capsules, extended-release tablets, extended-release core tablets, or controlled extended-release capsules may be preferred because of less frequent dosing and potentially smoother blood pressure control.

The hypotensive effect of verapamil is usually evident within the first week of therapy. The need for upward titration of dosage with the extended-release capsules or tablets should be based on blood pressure determinations made approximately 24 hours after a dose. When verapamil hydrochloride is administered at bedtime as extended-release core tablets or controlled extended-release capsules, blood pressure determinations the following morning or early afternoon are necessary to determine maximum effect.

Verapamil Therapy

The usual adult dosage of verapamil hydrochloride as extended-release capsules or tablets is 120-240 mg daily in the morning. Patients who may have an increased response to the drug, such as geriatric patients and those with small stature, may respond to 120 mg daily administered as extended-release capsules or tablets in the morning. Dosage of the drug should be adjusted according to the patient's blood pressure response. If an adequate response is not obtained with 120-240 mg daily as extended-release capsules or tablets, dosage may be increased in 120-mg increments. Thus, patients receiving 120 mg daily as extended-release tablets can have their dosage initially increased to 240 mg daily in the morning. For those receiving 180 mg daily, dosage initially can be increased to 240 mg in the morning; 180 mg in the morning and 180 mg in the evening; 240 mg in the morning and 120 mg in the evening; or 240 mg every 12 hours. Those receiving 240 mg daily can have their dosage initially increased to 180 mg in the morning and 180 mg in the evening or to 240 mg in the morning and 120 mg in the evening. If an adequate response is not obtained at this latter dosage level, dosage of the extended-release tablets may be increased to 240 mg every 12 hours. For patients receiving 120 mg daily as extended-release capsules, dosage may be increased to 240 mg daily in the morning, and for those receiving 240 mg daily, dosage may be increased to 360 mg daily in the morning. If an adequate response is not achieved at this latter dosage level, dosage of the extended-release capsules may be increased to 480 mg daily in the morning.

The usual initial adult dosage of verapamil hydrochloride extended-release core tablets (Covera-HS) is 180 mg daily at bedtime. If adequate response does not occur in patients receiving 180 mg daily as extended-release core tablets (Covera-HS), dosage may be increased to 240 mg daily, and subsequently dosage may be increased by 120-mg increments to 480 mg daily at bedtime. Some experts recommend a usual dosage range of 120-360 mg once daily for this preparation.

The usual initial adult dosage of verapamil controlled extended-release capsules (VerelanPM) is 200 mg daily at bedtime. Dosage may be increased to 300 mg daily at bedtime; if an adequate response is not achieved, dosage of the controlled extended-release capsules may be further increased to 400 mg (two 200-mg capsules) daily at bedtime.

Alternatively, if a conventional (immediate-release) preparation is used for the management of hypertension in adults, the usual initial oral dosage of verapamil hydrochloride as monotherapy is 40 mg twice daily to 80 mg 3 times daily. Initiation of therapy with dosages at the lower end of this range should be considered in patients who might respond to low dosages, such as geriatric patients and those with small stature. Oral dosages up to 480 mg daily have been used in some adults, but there is no evidence that dosages exceeding 360 mg daily as conventional tablets provide any additional benefit in the management of hypertension. Some experts recommend a usual dosage range of 80-320 mg daily (given in 2 divided doses) as conventional tablets.

When switching from conventional verapamil hydrochloride tablets to extended-release capsules or tablets, the total daily dose may remain the same.

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Target dosages generally can be achieved within 2-4 weeks, but it may take up to several months. Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with verapamil monotherapy, another antihypertensive agent with demonstrated benefit may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents at optimal dosages, a third drug may be added. In patients who experience intolerable adverse effects with verapamil, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the calcium-channel blocker and initiate another class of antihypertensive agent.

Verapamil/Trandolapril Fixed-combination Therapy

When combination therapy is required for the management of hypertension, the commercially available preparations containing verapamil in fixed combination with trandolapril should not be used for initial therapy. Instead, dosage should first be adjusted by administering each drug separately. If it is determined that the optimum maintenance dosage corresponds to the ratio in a commercial combination preparation, the fixed combination may be used. For patients receiving verapamil hydrochloride (up to 240 mg) and trandolapril (up to 8 mg) in separate tablets once daily, replacement with the fixed combination can be attempted using tablets containing the same component doses. Clinical trials with the verapamil and trandolapril fixed combination have investigated only once-daily dosing. The fixed-combination tablets contain verapamil hydrochloride in an extended-release component and trandolapril in an immediate-release component. The antihypertensive effect or the adverse effects of adding 4 mg once daily of trandolapril to extended-release verapamil hydrochloride (120 mg twice daily) have not been studied, nor have the effects of adding 180 mg of verapamil hydrochloride extended-release tablets daily to 1 mg of trandolapril twice daily been evaluated. Over the dosage range of extended-release verapamil hydrochloride of 120-240 mg once daily and trandolapril 0.5-8 mg once daily, the effects of the fixed combination increase with increasing doses of either component.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of verapamil hydrochloride is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on a consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

For additional information on initiating and adjusting verapamil hydrochloride dosage in the management of hypertension, .

Dosage in Hepatic and Renal Impairment

Patients with impaired hepatic and/or renal function should be monitored for prolongation of the PR interval on ECG, blood pressure changes, or other signs of overdosage during therapy with verapamil hydrochloride. Neither verapamil nor norverapamil appear to be removed appreciably by hemodialysis; therefore, supplemental doses in patients undergoing hemodialysis are not necessary.

Because approximately 70% of a dose of verapamil is excreted renally as metabolites (norverapamil, the principal metabolite, is pharmacologically active) in patients with normal renal function, the manufacturers recommend that the drug be used cautiously and with close monitoring in patients with impaired renal function pending further accumulation of data. Some evidence suggests that the pharmacokinetics of the drug may not be altered substantially in patients with impaired renal function; however, the manufacturer of the controlled extended-release capsules (VerelanPM) states that an initial dosage of 100 mg daily at bedtime rarely may be necessary in patients with impaired renal function.

In adults with severe hepatic impairment, dose and/or frequency of administration of verapamil hydrochloride must be modified according to the degree of impairment and the tolerance and therapeutic response of the patient. Usual oral daily doses for adults may need to be reduced by up to 60-70% in adults with severe hepatic dysfunction. The manufacturer of the controlled extended-release capsules (VerelanPM) states that an initial dosage of 100 mg daily at bedtime rarely may be necessary in patients with impaired hepatic function.

Cautions

Verapamil shares the toxic potentials of the calcium-channel blocking agents, and the usual precautions of these agents should be observed. In therapeutic dosage, verapamil usually is well tolerated. Serious adverse effects requiring dosage reduction occur in 6.3% of patients receiving the drug orally; adverse effects requiring discontinuance of oral verapamil occur in approximately 5.5% of patients. The incidence and severity of adverse effects are increased in patients receiving the drug IV; in patients with hypertrophic cardiomyopathy, moderate to severe congestive heart failure, or sick sinus syndrome; and in patients receiving β-adrenergic blocking agents or digoxin concurrently with verapamil.

Cardiovascular Effects

Serious adverse effects attributed to verapamil's action on the cardiac conduction system occurring in less than 2% of patients include bradycardia; first-, second-, and third-degree AV block; AV dissociation; and bundle-branch block. First-degree AV block may be asymptomatic. Prolongation of the PR interval is correlated with plasma verapamil concentrations, especially during initial titration of therapy with the drug, but this correlation may disappear during chronic therapy. When first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms, occur with oral verapamil, they usually are associated with peaks in serum concentrations of the drug. In patients with hypertrophic cardiomyopathy receiving the drug orally, the incidence of these adverse effects may be increased; in one study, 11% of these patients had bradycardia, 4% had second-degree AV block, and 2% had sinus arrest. Cardiovascular collapse, which may be fatal, has occurred rarely in patients receiving verapamil for hypertrophic cardiomyopathy and may be related to electrophysiologic and/or hemodynamic effects of the drug. Asystole has occurred with IV verapamil but AV nodal or normal sinus rhythm usually has returned within a few seconds. Conduction disturbances, including marked first-degree block or progression to second- or third-degree block, generally respond to discontinuance of IV verapamil, reduction of oral verapamil dosage, or, in the case of increased ventricular response rate, to cardioversion; severe AV block may rarely require discontinuance of the drug and initiation of appropriate treatment (e.g., IV atropine, isoproterenol, calcium), depending on the clinical situation. During clinical trials, ventricular rates less than 50 bpm and asymptomatic hypotension occurred in 15 and 5%, respectively, of patients with atrial fibrillation or flutter receiving verapamil and cardiac glycoside therapy to control ventricular response.

In patients with atrial fibrillation and/or flutter and an accessory AV pathway (e.g., Wolff-Parkinson-White or Lown-Ganong-Levine syndrome), increased anterograde conduction across aberrant pathways that bypass the AV node may result in a verapamil-induced increase in ventricular response rate. Ventricular fibrillation with loss of consciousness and atrial fibrillation with markedly increased ventricular response rate and resultant profound hypotension and syncope have occurred within minutes after IV administration of verapamil in patients with an accessory AV pathway. The risk of these effects occurring when the drug is used orally in patients with atrial fibrillation and/or flutter and an accessory AV pathway has not been established, but a similar risk may be associated with oral use of the drug. Because of the risk of potentially fatal adverse effects, verapamil should not be used (parenterally or orally) in these patients. (See Cautions: Precautions and Contraindications.)

Congestive heart failure or pulmonary edema, resulting from verapamil's negative inotropic action, occurs in less than 2% of patients receiving the drug orally. Most patients who develop congestive heart failure or pulmonary edema require reduction of verapamil dosage or discontinuance of the drug.

Adverse effects attributed to the vasodilating action of verapamil on vascular smooth muscle include dizziness or symptomatic hypotension, which occur in less than 4% of patients receiving the drug. Systolic and diastolic blood pressures less than 90 and 60 mm Hg, respectively, occur in 5-10% of patients receiving IV verapamil. Hypotension rarely may require treatment with an IV calcium salt (e.g., 7-14 mEq of calcium in adults) or vasopressor (e.g., dopamine, isoproterenol, metaraminol, methoxamine, norepinephrine, phenylephrine). Pretreatment with IV calcium chloride may prevent the hemodynamic changes associated with IV verapamil. Decreases in blood pressure to lower than normal are unusual in hypertensive patients receiving the drug.

Peripheral edema occurs in about 2% of patients receiving the drug orally and flushing occurs occasionally. Myocardial infarction has occurred in 1% or less of patients receiving oral verapamil, principally in those being treated for unstable angina; however, it is difficult to conclude whether this effect is drug related or associated with the natural history of the underlying disease. Angina, chest pain, palpitation, syncope, and claudication have also been reported in 1% or less of patients receiving oral verapamil but has not been directly attributed to the drug.

GI Effects

The most common adverse effect of oral verapamil is constipation, occurring in less than 9% of patients. Nausea, dyspepsia, and abdominal discomfort occur in less than 3% of patients receiving the drug orally and in less than 1% receiving the drug IV. Dry mouth, gingival hyperplasia, GI distress, and diarrhea have been reported in 1% or less of patients receiving the drug orally but have not been directly attributed to the drug. Paralytic ileus, which was reversible following discontinuance of the drug, has been reported rarely in patients receiving verapamil.

Nervous System Effects

Dizziness occurs in about 4% of patients receiving verapamil orally and in less than 2% of patients receiving the drug IV. Headache, lethargy, and fatigue occur in about 5, 3, and less than 2% of patients receiving oral verapamil, respectively; headache has occurred in less than 2% of patients receiving the drug IV. Seizures have occurred occasionally following IV administration of the drug.

Confusion, sleep disturbances (e.g., insomnia), sleepiness, equilibrium disorders, muscle cramps, paresthesia, shakiness, cerebrovascular accident, and psychotic symptoms have been reported in patients receiving oral verapamil but many of these have not been directly attributed to the drug. Similarly, mental depression, sleepiness, muscle fatigue, and vertigo have been reported with, but not directly attributed to, IV verapamil. Vivid, disturbing dreams, which recurred with rechallenge, have been reported in several patients receiving the drug for migraine headache prophylaxis. Morbid dreams (paroniria) also have been reported in several other patients receiving the drug.

Hepatic Effects

Transient increases in serum concentrations of AST (SGOT) and ALT (SGPT), with or without concomitant increases in alkaline phosphatase and bilirubin, have been reported rarely with oral verapamil. These increases are occasionally transient and may resolve despite continued verapamil therapy. However, hepatocellular injury, which recurred during rechallenge, has occurred in several patients and may be accompanied by clinical symptoms of hepatotoxicity, including malaise, fever, and/or right upper quadrant pain. Periodic monitoring of liver function is recommended during chronic verapamil therapy.

Other Adverse Effects

Blurred vision, tinnitus, dyspnea, hair loss, rash and arthralgia, Stevens-Johnson syndrome, erythema multiforme, macular eruptions, ecchymosis, bruising, purpura (vasculitis), exanthema, urticaria, hyperkeratosis, gynecomastia, urinary frequency, impotence, and spotty menstruation have been reported in approximately 1% of patients receiving oral verapamil, but some of these have not been directly attributed to the drug; myalgia also have been reported. Diaphoresis has been reported occasionally in patients receiving the drug IV or orally, and rotary nystagmus has been reported in a few patients receiving the drug IV. Rarely, hypersensitivity to verapamil has been manifested as bronchospasm and/or laryngospasm accompanied by pruritus and urticaria. Hyperprolactinemia, with or without galactorrhea, has occurred occasionally in females receiving verapamil; these effects were not associated with amenorrhea and subsided following discontinuance of the drug.

Precautions and Contraindications

Some findings concerning possible risks of calcium-channel blocking agents have raised concerns about the safety and efficacy of these agents (mainly conventional [short-acting] preparations of nifedipine). Findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared long-term therapy with a dihydropyridine-derivative calcium-channel blocker, a thiazide-like diuretic, or an angiotensin-converting enzyme (ACE) inhibitor, however, have failed to support these findings.

Verapamil shares the toxic potentials of other nondihydropyridine calcium-channel blocking agents, and the usual precautions of these agents should be observed.

IV verapamil initially should only be used in a hospital setting using ECG and hemodynamic monitoring and where resuscitative therapy and equipment (e.g., direct-current cardioverter) are readily available. Once the physician becomes familiar with an individual patient's response to verapamil, the drug may be administered IV in an office setting. All patients receiving IV verapamil should be monitored electrocardiographically.

Because verapamil decreases peripheral vascular resistance and occasionally causes symptomatic hypotension, blood pressure should be monitored carefully.

Certain verapamil extended-release tablets (e.g., Covera-HS) are nondeformable and therefore should be used with caution in patients with preexisting severe GI narrowing.

Verapamil should be used with caution or not at all in patients with moderately severe to severe ventricular dysfunction or heart failure since the drug may precipitate or worsen heart failure. Signs and symptoms of heart failure in these patients should be controlled with a cardiac glycoside (e.g., digoxin) (see Drug Interactions: Digoxin) and/or diuretics before initiating verapamil therapy. The drug should also be used with caution in patients with hypertrophic cardiomyopathy since serious and sometimes fatal adverse cardiovascular effects (e.g., pulmonary edema, hypotension, second-degree AV block, sinus arrest) have occurred in such patients during verapamil therapy.

Dosage should be reduced, verapamil discontinued, and/or appropriate therapy or resuscitative measures instituted if congestive heart failure or conduction disturbances occur. (See Cautions: Cardiovascular Effects.)

Verapamil should be used with caution in patients with hepatic or renal impairment. Some clinicians state that extended-release preparations of verapamil hydrochloride should be used with caution in patients with renal impairment, since serious adverse (e.g., cardiovascular, metabolic, hepatic) effects secondary to accumulation of the drug and/or its metabolites have been reported in some of these patients. When the drug is administered orally or when multiple IV doses are given to these patients, the usual dosage should generally be reduced and the patient should be carefully monitored for signs (e.g., prolongation of the PR interval) and symptoms of overdosage. Because of the apparent potential for verapamil-induced hepatocellular toxicity, liver function should be determined periodically during chronic verapamil therapy.

Although verapamil has been used in a limited number of patients with pseudohypertrophic (Duchenne type) muscular dystrophy, only minimal ergometric benefit was apparent during therapy with the drug, and the manufacturers state that verapamil should be used with caution in patients with this condition since the drug can precipitate respiratory paralysis. Caution should also be exercised and appropriate monitoring performed when verapamil is used in patients with supratentorial tumors who are undergoing anesthesia induction, since increased intracranial pressure can occur.

Patients with sick sinus syndrome and patients with atrial flutter and/or fibrillation with an accessory bypass tract are at increased risk of developing conduction disturbances during verapamil therapy. The drug should not be used for the management of atrial flutter or fibrillation in patients with an accessory bypass tract (e.g., those with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome) since life-threatening adverse effects (e.g., ventricular fibrillation, cardiac arrest) may be precipitated secondary to accelerated AV conduction. Verapamil also should not be used in patients with ventricular tachycardia, since administration of the drug in patients with wide-complex ventricular tachycardia (QRS of 0.12 seconds or longer) can result in marked hemodynamic deterioration and ventricular fibrillation; proper diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative when administration of verapamil is considered.

Verapamil generally should not be used in patients with severe left ventricular dysfunction (i.e., pulmonary wedge pressure greater than 20 mm Hg, left ventricular ejection fraction less than 20-30%), unless the heart failure is caused by a supraventricular tachycardia amenable to verapamil, nor should the drug be used in patients with moderate to severe symptoms of cardiac failure. The drug also should generally not be used in patients with ventricular dysfunction or AV conduction abnormalities if they are receiving a β-adrenergic blocking agent. Verapamil is contraindicated in patients with severe hypotension (systolic blood pressure less than 90 mm Hg) or cardiogenic shock and, unless a functioning artificial ventricular pacemaker is in place, in patients with second- or third-degree AV block or with sick sinus syndrome. Verapamil also is contraindicated in patients with known hypersensitivity to the drug. Some experts state that verapamil is contraindicated in patients with borderline hypotension associated with drug-induced hemodynamically significant tachycardia, because the drug may further lower blood pressure.

Pediatric Precautions

Controlled studies with verapamil in children have not been performed to date, but experience using IV verapamil in more than 250 children (about 50% were younger than 12 months of age and 25% were neonates) indicates that the drug produces effects similar to those in adults. However, severe adverse cardiovascular effects (e.g., refractory hypotension, cardiac arrest) have occurred rarely following IV administration of verapamil in neonates and infants. Therefore, the manufacturer states that IV verapamil should be used with caution in neonates and infants. However, some experts state that IV verapamil should not be used in infants. These experts also state that IV verapamil should be used with caution in children because such use also may result in adverse cardiovascular effects (e.g., hypotension, myocardial depression). Safety and efficacy of oral verapamil in children younger than 18 years of age have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, .

Mutagenicity and Carcinogenicity

At a concentration of 3 mg/plate, verapamil was not mutagenic in the Ames microbial mutagen test with or without metabolic activation.

Studies in rats using verapamil dosages of 6 times the recommended maximum human dosage for 18 months did not reveal evidence of carcinogenicity. There was also no evidence of carcinogenic potential in rats receiving oral verapamil hydrochloride dosages approximately 1, 3.5, and 12 times the recommended maximum human dosage for 2 years.

Pregnancy, Fertility, and Lactation

Pregnancy

Reproduction studies in rabbits and rats using oral verapamil dosages up to 1.5 (15 mg/kg daily) and 6 (60 mg/kg daily) times the usual human oral dosage, respectively, have not revealed evidence of teratogenicity. However, in rats, this dosage has been shown to be embryocidal and was associated with retarded fetal growth and development, probably as a result of adverse maternal effects as evidenced by reduced maternal weight gain; this dosage has been shown to cause hypotension in rats. There are no adequate and controlled studies to date using verapamil in pregnant women, and the drug should be used during pregnancy only when clearly needed. Although the effects of verapamil on the mother and fetus during labor and delivery have not been fully determined, the drug has been used short-term without prolonging the duration of labor or increasing the need for forceps delivery or other obstetric intervention and without apparent adverse fetal effect in women who received verapamil as therapy for adverse cardiac effects induced by β-adrenergic agonists that were used in the management of premature labor.

Fertility

Reproduction studies in female rats using oral verapamil hydrochloride dosages up to 5.5 times the recommended maximum human dosage have not revealed evidence of impaired fertility. The effects of verapamil on male fertility have not been determined, but the drug has increased human sperm motility in vitro.

Lactation

Verapamil is distributed into milk. Because of the potential for serious adverse effects of verapamil in nursing infants, the manufacturers recommend that nursing be discontinued during therapy with the drug.

Drug Interactions

Protein-bound Drugs

Because verapamil is highly protein bound, it theoretically could be displaced from binding sites by, or could displace from binding sites, other protein-bound drugs such as oral anticoagulants, hydantoins, salicylates, sulfonamides, and sulfonylureas. Verapamil should be used with caution in patients receiving any highly protein-bound drug.

β-Adrenergic Blocking Agents

Concomitant use of nondihydropyridine calcium-channel blocking agents (e.g., verapamil, diltiazem, mibefradil [no longer commercially available in the US]) and β-adrenergic blocking agents can have additive negative effects on myocardial contractility, heart rate, and AV conduction. The incidence of congestive heart failure (CHF), arrhythmia, and severe hypotension may be increased when verapamil is administered concurrently with a β-adrenergic blocking agent (e.g., propranolol), especially if high doses of the latter agent are used, if the drugs are administered IV, or if the patient has moderately severe or severe CHF (e.g., left ventricular ejection fraction less than 20-30%), severe cardiomyopathy, or recent myocardial infarction. In several studies in patients with chronic stable angina whose symptoms were inadequately controlled by conventional therapy, concomitant administration of verapamil and a β-adrenergic blocking agent (i.e., propranolol) resulted in greater antianginal effect than either drug alone; patients studied were usually refractory to propranolol or intolerant of its adverse effects. When low or moderate dosages of propranolol (i.e., 320 mg or less daily) were used concomitantly with verapamil, substantial negative inotropic, chronotropic, or dromotropic effects generally were not produced by combined therapy in patients with preserved left ventricular function; however, such effects have occurred in some patients.

Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil, principally in geriatric patients and in association with concomitant β-adrenergic blocker therapy. . The hypotensive effects of concomitant therapy with verapamil and a β-adrenergic blocking agent are usually additive; this effect has been used to therapeutic advantage in some hypertensive patients, but careful adjustment of dosage is necessary. However, excessive bradycardia and AV block, including complete heart block, occasionally have occurred in hypertensive patients receiving combined therapy with the drugs, and the risks of such combined hypotensive therapy may outweigh the benefits. Verapamil should be used cautiously with a β-adrenergic blocking agent for the management of hypertension and only with close monitoring.

Patients considered for combined therapy with verapamil and a β-adrenergic blocking agent must be carefully selected and monitored. Pending further accumulation of data, concomitant therapy with the drugs should generally be avoided or used with extreme caution after conventional therapy has failed in patients with any degree of left ventricular dysfunction, patients with AV conduction abnormalities, and patients receiving drugs with a negative inotropic effect. If verapamil is used with a β-adrenergic blocking agent, the possibility of detrimental interactions on myocardial contractility or AV conduction should be considered, dosage of both drugs may need to be reduced, the clinical status of the patient should be carefully monitored, and the need for concomitant therapy should be reassessed periodically. Because of the depressant effects of the drugs on myocardial contractility and AV conduction, IV verapamil and an IV β-adrenergic blocking agent should not be administered within a few hours of each other.

Severe bradycardia (e.g., 36 bpm), which was associated with a wandering atrial pacemaker in one patient, and transient asystole have been reported when oral verapamil and ophthalmic timolol were used concomitantly. A single IV dose of atropine was effective in managing serious bradycardia in at least one patient. Verapamil should be used with extreme caution in patients receiving ophthalmic timolol; when therapy with a calcium-channel blocking agent is indicated (e.g., for angina) in such patients, an agent with minimal effects on the sinoatrial node and cardiac conduction (e.g., nifedipine) should be used if possible.

Verapamil may substantially increase the oral bioavailability of metoprolol, a lipophilic drug. Area under the plasma metoprolol concentration-time curve has increased up to 300% following initiation of verapamil therapy. Verapamil appears to increase oral bioavailability of metoprolol by decreasing its hepatic clearance, although the exact mechanism(s) has not been elucidated. A similar pharmacokinetic interaction does not appear to occur when atenolol (a hydrophilic drug) and verapamil are used concomitantly, although long-term administration of verapamil may increase steady-state plasma concentrations of atenolol. Concomitant use of verapamil and metoprolol should be avoided if possible and another β-adrenergic blocker with which verapamil does not interact pharmacokinetically (e.g., atenolol) preferably used when combined therapy is required. If verapamil and metoprolol are used concomitantly, dosage of metoprolol should be adjusted carefully and the patient monitored closely. Verapamil also may decrease oral clearance of propranolol; minimal increases in plasma propranolol concentrations have been reported in some individuals receiving verapamil concomitantly.

Digoxin

Oral verapamil may increase serum digoxin concentrations by 50-75% during the first week of verapamil therapy. This effect may be more substantial in patients with underlying hepatic disease (e.g., cirrhosis). When verapamil is administered to a patient receiving digoxin, dosage of the glycoside generally should be reduced and the patient monitored closely for clinical response and cardiac glycoside toxicity. Combined therapy with the drugs is usually well tolerated if dosages of digoxin are properly adjusted. Whenever cardiac glycoside toxicity is suspected, dosage of digoxin should be further reduced and/or temporarily withheld. If verapamil is discontinued in a patient stabilized on digoxin, the patient should be monitored closely and dosage of the glycoside increased as necessary to avoid underdigitalization. Because of the possibility of additive effects of verapamil and digoxin on AV nodal conduction, patients receiving the drugs concomitantly should undergo periodic ECG monitoring for AV block or severe bradycardia during chronic therapy.

Hypotensive Agents

Verapamil may be additive with or potentiate the hypotensive actions of hypotensive agents (e.g., diuretics, angiotensin-converting enzyme inhibitors, vasodilators). This effect is usually used to therapeutic advantage in hypertensive patients, but careful adjustment of dosage is necessary when these drugs are used concomitantly. An excessive reduction in blood pressure may occur in patients receiving verapamil concomitantly with drugs that attenuate α-adrenergic response (e.g., methyldopa, prazosin). In healthy normotensive individuals, 160 mg of oral verapamil hydrochloride substantially enhanced the hypotensive effect of 1 mg of oral prazosin. Patients receiving verapamil for the management of hypertension concomitantly with a hypotensive agent that inhibits α-adrenergic activity should be monitored closely for an exaggerated hypotensive effect.

Antiarrhythmic Agents

A substantial hypotensive effect has occurred in some patients with hypertrophic cardiomyopathy when verapamil was used concurrently with quinidine; pending further accumulation of data on the safety of combined therapy, concomitant use of verapamil and quinidine in such patients should probably be avoided. Excessive hypotension has also been reported following an IV dose of verapamil in several other patients who were receiving quinidine therapy concomitantly but did not have hypertrophic cardiomyopathy. There is in vitro evidence that verapamil and quinidine have additive adrenergic-blocking activity at α₁- and α₂-receptors. Verapamil and quinidine have reportedly been used effectively in combination in a limited number of patients for the treatment of atrial fibrillation; verapamil has counteracted the effects of quinidine on AV conduction. The drugs have been used concomitantly in these patients without serious adverse effects; however, controlled studies to determine the safety and efficacy of this combination have not been conducted to date and the drugs should be used concomitantly with caution. There is also evidence that verapamil may substantially increase plasma quinidine concentrations during concomitant use. In one patient, the elimination half-life and peak and steady-state plasma concentrations of quinidine increased and clearance and volume of distribution decreased during verapamil therapy, requiring a reduction in quinidine dosage; an increase in quinidine dosage was subsequently necessary when verapamil was discontinued after 5 months of combined therapy.

Disopyramide should not be administered concomitantly with IV or oral verapamil because of the possibility of additive effects and impairment of left ventricular function. Pending further accumulation of data on the safety of combined therapy, disopyramide should be discontinued 48 hours prior to initiating verapamil therapy and should not be reinstituted until 24 hours after verapamil has been discontinued.

Carbamazepine

Concomitant use of verapamil and carbamazepine may result in increased plasma carbamazepine concentrations and subsequent toxicity. In several patients receiving 1-2 g of carbamazepine daily, initiation of 360 mg of verapamil hydrochloride daily resulted in development of neurologic manifestations (e.g., diplopia, dizziness, ataxia, nystagmus) of carbamazepine toxicity within 36-96 hours. Plasma total and unbound carbamazepine concentrations increased by a mean of 46 and 33%, respectively, but returned to baseline values within 1 week after discontinuance of verapamil; manifestations of toxicity also resolved during this period. The ratio of plasma carbamazepine 10,11-epoxide to unchanged drug decreased during verapamil therapy but returned toward pretreatment levels following discontinuance of verapamil. Limited experience suggests that a similar interaction may also occur when diltiazem, but not nifedipine, is administered concomitantly with carbamazepine. It appears that verapamil and possibly diltiazem inhibit hepatic metabolism of carbamazepine via the cytochrome P-450 microsomal enzyme system.

If verapamil is initiated in patients receiving carbamazepine, a 40-50% reduction in carbamazepine dosage may be necessary during concomitant therapy. Patients should be monitored closely for manifestations of carbamazepine toxicity and for alterations in the pharmacokinetics of carbamazepine during concomitant therapy, adjusting carbamazepine dosage accordingly. If verapamil is discontinued, dosage of carbamazepine should be increased to avoid loss of seizure control.

Rifampin

Rifampin may substantially reduce the oral bioavailability of verapamil. In a patient receiving 600 mg of rifampin daily, the patient's arrhythmias were resistant to oral verapamil therapy, requiring a verapamil hydrochloride dosage of 1920 mg daily. Steady-state trough serum concentrations of verapamil were 123 ng/mL at this dosage during rifampin use; 9 days after discontinuance of rifampin, trough serum verapamil concentrations increased almost fourfold. Arrhythmias were subsequently controlled at a lower verapamil dosage. It appears that rifampin may decrease oral bioavailability of verapamil by increasing first-pass metabolism via induction of hepatic microsomal enzymes. Patients receiving verapamil should be monitored closely for reduced clinical efficacy or for toxicity whenever rifampin is initiated or discontinued, respectively, and dosage of verapamil should be adjusted accordingly; the effects of this interaction may persist for several days or longer following discontinuance of rifampin.

Cimetidine

Several manufacturers state that the pharmacokinetics of IV verapamil are not affected by concomitant use of cimetidine. However, conflicting data regarding the effects of cimetidine on clearance of IV or oral verapamil and on bioavailability of oral verapamil have been reported. Studies to date have determined the effects of cimetidine on single IV or oral doses of verapamil and may not reflect the effects during multiple-dose verapamil therapy. Pending further accumulation of data from well-designed studies performed under steady-state conditions for verapamil, some clinicians recommend that patients receiving verapamil should be monitored closely for alterations in the drug's pharmacokinetics and therapeutic and toxic effects whenever cimetidine is added to or deleted from the drug regimen and that verapamil dosage should be reduced if necessary (e.g., if oral bioavailability is increased and/or clearance is decreased).

Lithium

Serum lithium concentrations may decrease, increase, or remain unchanged during concomitant use of verapamil. In a patient with bipolar disorder whose lithium dosage had been stabilized for several years, manic symptoms emerged and serum lithium concentrations decreased to subtherapeutic levels within 1 month after initiating 320 mg of verapamil hydrochloride daily, requiring an increase in lithium carbonate dosage from 900-1200 mg daily to 1800-2100 mg daily. Serum lithium concentrations also decreased in another patient and urinary excretion of the cation increased. Although the mechanism of this interaction currently is not known, serum lithium concentrations and the patient should be monitored closely and lithium dosage adjusted accordingly when verapamil is initiated or discontinued in patients receiving lithium therapy.

There is also some evidence that verapamil may potentiate the neurotoxic effects of lithium. When 240 mg of verapamil hydrochloride daily was initiated as investigational antimanic therapy in a patient whose bipolar disorder was inadequately controlled with a therapeutic dosage of lithium, bipolar disorder was controlled within 1 week after initiating combined therapy, but manifestations of neurotoxicity occurred 2 days later despite therapeutic serum lithium concentrations. Neurotoxicity subsided within 2 days following discontinuance of verapamil but recurred when the patient was rechallenged with verapamil in an attempt to regain control of the bipolar disorder. Verapamil did not appear to affect the pharmacokinetics of lithium in this patient. The mechanism of this interaction is not known, but a similar interaction has been described in a patient receiving lithium and diltiazem concomitantly. Calcium-channel blocking agents appear to share some of the neuropharmacologic effects of lithium, and combined therapy with the drugs may potentiate neurotoxicity. Pending further accumulation of data, verapamil and possibly other calcium-channel blocking agents should be used concomitantly with lithium cautiously.

Flecainide

Experience with combined use of verapamil and flecainide is limited. In a small number of healthy individuals, concomitant administration of verapamil and flecainide showed possible additive effects on myocardial contractility. Because flecainide also has a negative inotropic effect and decreases AV nodal conduction, the manufacturer of flecainide cautions that flecainide and verapamil not be used concomitantly unless the potential benefits are considered to outweigh the risk.

Theophylline

Concomitant use of verapamil in individuals receiving theophylline has resulted in decreased clearance of theophylline, elevated serum theophylline concentrations, and a prolonged serum half-life of the bronchodilator. Patients receiving theophylline should be closely monitored for signs of theophylline toxicity when verapamil is administered concomitantly; serum theophylline concentrations should be monitored and dosage of the bronchodilator reduced if indicated.

Alcohol

Verapamil may increase blood alcohol concentrations and prolong its effects. Following oral administration of a single oral dose of alcohol (e.g., 0.8 g/kg of body weight) to healthy men receiving verapamil (80 mg 3 times daily for 5 days) or placebo, mean peak blood alcohol concentrations increased by 17% and the area under the blood alcohol concentration-time curve (AUC_0-12) increased by 30%.

Other Drugs

Verapamil can produce marked increases in blood cyclosporine concentrations. Therefore, the drugs should be used concomitantly with caution; patients should be monitored closely for possible cyclosporine toxicity, and dosage of the drug should be adjusted accordingly.

Verapamil and a neuromuscular blocking agent should be used concomitantly with caution since there is some evidence that verapamil may potentiate the neuromuscular blockade of these agents. Careful monitoring of neuromuscular function is necessary, and dosage of verapamil and/or the neuromuscular blocking agent should be decreased as necessary.

The manufacturers state that dosages of each agent should be titrated carefully when a calcium slow-channel blocking agent such as verapamil is used concomitantly with inhalation anesthetics that depress cardiovascular activity since potentiation of this depression may occur.

Phenobarbital can increase the clearance of total and unbound verapamil, possibly via induction of hepatic cytochrome P-450 microsomal metabolism. Combined therapy with the drugs may decrease oral bioavailability of verapamil secondary to increased first-pass metabolism in the liver. The possibility that verapamil dosage may need to be adjusted following initiation or discontinuance of barbiturate therapy should be considered.

The clinical relevance to humans is not known, but animal studies suggest that concomitant use of IV verapamil and IV dantrolene may result in cardiovascular collapse.

Pharmacokinetics

In all studies described in the Pharmacokinetics section, verapamil was administered as the hydrochloride salt.

Absorption

Approximately 90% of an oral dose of verapamil hydrochloride is rapidly absorbed from the GI tract following oral administration of conventional tablets of the drug. Only about 20-35% of an oral dose reaches systemic circulation as unchanged drug following administration of conventional tablets since verapamil is metabolized on first pass through the liver. The manufacturers state that oral bioavailability of extended-release capsules or tablets of the drug is similar to that of the conventional tablets when the drug is administered under fasting conditions. Oral bioavailability of the drug may be substantially increased in patients with hepatic dysfunction (e.g., in those with hepatic cirrhosis).

Considerable interindividual and intraindividual variations in plasma concentrations attained with a specific oral dose of verapamil have been reported. In healthy adults, peak plasma concentrations are reached within 1-2 hours after oral administration of conventional tablets of the drug, within 7-9 or 4-8 hours after extended-release capsules or tablets, respectively, and within about 11 hours after extended-release core tablets or controlled extended-release capsules. Following oral administration of a single 240-mg extended-release capsule or tablet under fasting conditions, mean peak plasma verapamil concentrations of about 77 or 150-165 ng/mL, respectively, were achieved, but there was considerable interindividual variation. Food decreases the rate and extent of absorption of extended-release verapamil tablets but produces smaller differences between peak and trough plasma concentrations of the drug; food does not appear to substantially affect the absorption of conventional tablets, extended-release capsules, extended-release core tablets, or controlled extended-release capsules. of the drug. Mean steady-state plasma concentrations of verapamil range from 125-400 ng/mL following long-term oral administration of 120 mg every 6 hours as conventional tablets in healthy adults. Peak plasma concentrations after a 10-mg IV dose of verapamil range from 10-1500 ng/mL. In a limited number of infants receiving 1-3 mg/kg of the drug orally every 8 hours, peak plasma verapamil concentrations were attained within 1-4 hours after a dose but varied considerably, ranging from about 30-150 ng/mL.

Plasma concentrations greater than 100 ng/mL usually are required for acute antiarrhythmic effect, and PR-interval prolongation linearly correlates with plasma verapamil concentrations ranging from 10-250 ng/mL during initial dose titration, but this correlation may disappear during chronic therapy. Hemodynamic effects of verapamil usually peak at about 2 hours and persist for 6-8 hours after a single oral dose of the drug as conventional tablets. After a single IV injection of verapamil, hemodynamic effects peak within 5 minutes and persist for 10-20 minutes; effects on the AV node occur within 1-2 minutes, peak at 10-15 minutes, and usually persist for 30-60 minutes, but may persist for as long as 6 hours. No relationship has been established between plasma verapamil concentrations and blood pressure reduction.

Distribution

The steady-state volume of distribution of verapamil ranges from 4.5-7 L/kg in healthy adults. An apparent volume of distribution of 12 L/kg has been reported in patients with hepatic cirrhosis. Approximately 90% of verapamil is bound to plasma proteins. Verapamil and norverapamil distribute into the CNS. Following oral administration of 120 mg of the drug 4 times daily in several schizophrenic patients, mean CSF concentrations of verapamil and norverapamil were 6 and 4%, respectively, of mean plasma concentrations.

Verapamil crosses the placenta and is present in umbilical vein blood at delivery. The drug is distributed into milk, reaching concentrations in breast milk similar to those in maternal plasma in some women.

Elimination

Plasma concentrations of verapamil appear to decline in a biphasic or triphasic manner following IV administration of the drug. After IV infusion or administration of a single oral dose, verapamil has a plasma half-life of 2-8 hours. After 1-2 days of oral administration of the drug, plasma half-life may increase to 4.5-12 hours, presumably because of saturation of hepatic enzymes. Plasma half-life of the drug also is increased to 14-16 hours in patients with hepatic cirrhosis. Plasma elimination half-life also appears to be increased and clearance is decreased in geriatric patients. An elimination half-life of 4.4-6.9 hours has been reported in several infants.

Verapamil is rapidly and almost completely metabolized in the liver to at least 12 dealkylated or demethylated metabolites; only norverapamil is present in plasma in more than trace amounts. The drug appears to undergo stereoselective first-pass metabolism, with the l-isomer being preferentially metabolized. Norverapamil, an active (approximately 20% of the cardiovascular activity of verapamil) metabolite, achieves plasma concentrations approximately equal to those of verapamil within 4-6 hours of administration. Food decreases the rate and extent of drug reaching systemic circulation as norverapamil following oral administration of extended-release verapamil tablets. Approximately 70 and 16% of an oral or IV dose are excreted as metabolites in urine and feces, respectively, within 5 days. Only 3-4% of a dose is excreted in urine as unchanged drug. Metabolism of verapamil may differ in infants; in several infants receiving the drug orally, plasma concentrations of norverapamil were only 50% those of unchanged drug, and concentrations of 2 inactive metabolites were similar to or exceeded those of unchanged drug. Neither verapamil nor norverapamil appear to be removed appreciably by hemodialysis.