Verapamil is used in the management of supraventricular tachycardias (SVTs).700,701 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.700,701 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.700 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.700 Verapamil should only be used in hemodynamically stable patients who do not have impaired ventricular function.700
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).700 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.118,171,181,182,183,184,185,186,187,188 The drug appears to be more effective in preventing PSVT associated with AV nodal reentry than that associated with a concealed accessory pathway.183,184,187,188
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.700,701 Management of atrial fibrillation or flutter depends on the clinical situation and the patient's condition.700,701 For acute treatment of atrial fibrillation, IV verapamil may be used to temporarily control rapid ventricular rate,701 usually decreasing heart rate by at least 20%. Cardioversion is indicated, however, in hemodynamically unstable patients.701 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.701 (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.
Calcium-channel blockers (i.e., verapamil or diltiazem) may be used for the management of atrial fibrillation associated with acute myocardial infarction (MI) in patients with a β-blocker intolerance.527,701 (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.118,171,172,173,174,175,176,177,178,179,180,181,182 Verapamil has also been used alone†172,173,174,176,177,178 and in combination with quinidine†180 to control ventricular rate in these patients. The drug should not be used when these arrhythmias are associated with an accessory bypass tract.118 Unlike cardiac glycosides, verapamil may be particularly useful in controlling tachycardia induced by exercise and stress.171,172,173,174,177,178,179 Verapamil reduces heart rate at rest (e.g., by 15-30%)172,173,174,175,176,177,178,179 and increases exercise capacity172,173,174,178 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.172,173,178,179,181 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.173,174 Combined therapy with verapamil and a cardiac glycoside appears to be somewhat more effective than verapamil172,174,176 or a cardiac glycoside172,173,178 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.381 (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.700
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.255,256,257,258,259,260,261,262,263,264,265,700 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.700 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).255,259,264,700 Therapy with verapamil has been associated with slowing of atrial261 and ventricular rates255,256,257,259,260,261,263 and conversion to sinus rhythm255,256,257,259,260,261 in some patients with this arrhythmia.255,256,259,700 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.700 Verapamil also may be useful orally for chronic suppression of recurrent symptomatic multifocal atrial tachycardia.256,257,261,265,700
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.700β-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.700
Angina
Verapamil is used in the management of angina, including chronic stable angina, unstable angina, and Prinzmetal variant angina.118,362,1100,1101 Calcium-channel blockers (used alone or in combination with nitrates) are considered the drugs of choice for the management of Prinzmetal variant angina.1100β-Blockers are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; however, calcium-channel blockers may be substituted or added in patients who do not tolerate or respond adequately to β-blockers.1101 In patients with chronic stable angina, verapamil may reduce the frequency of attacks, allow a decrease in sublingual nitroglycerin dosage, and increase exercise tolerance.1101 All classes of calcium-channel blockers appear to be equally effective in reducing anginal episodes; however, choice of a specific agent should be individualized since the pharmacologic properties of these drugs differ.1101 Verapamil also may be beneficial in patients with unstable angina; experts recommend the use of a nondihydropyridine calcium-channel blocker (e.g., diltiazem, verapamil) for the relief of ongoing or recurring ischemia when β-blocker therapy is inadequate, not tolerated, or contraindicated in patients with unstable angina who do not have clinically important left ventricular dysfunction, increased risk of cardiogenic shock, or AV block.1100
Although concurrent use of some calcium-channel blockers and a β-blocker may have beneficial effects in some patients (e.g., reduction of dihydropyridine-induced tachycardia through β-blockade), combined use of verapamil with a β-blocker generally should be avoided because of the potential adverse effects on AV nodal conduction, heart rate, and cardiac contractility.1101 (See Drug Interactions: β-Adrenergic Blocking Agents.)
Hypertension
Verapamil is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.117,118,281,282,352,354,360,1200
Calcium-channel blockers (e.g., verapamil) are considered one of several preferred antihypertensive drugs for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501,502,503,504,1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,504,1200,1213 (See Uses: Hypertension, in Amlodipine 24:28.08.)
Calcium-channel blockers may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina)195,212,281,285,286,523 and in geriatric patients, including those with isolated systolic hypertension.193,194,195,204,212,224,227,230,282,288,289,502,510 (See Uses: Hypertension, in Amlodipine 24:28.08.) 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.118,171,172,173,174,175,176,177,178,179,180,181,182,353,502,504 However, some experts recommend against the use of nondihydropyridine calcium-channel blockers in patients who have heart failure with reduced ejection fraction because of the drugs' myocardial depressant activity and unfavorable outcomes in some clinical trials in patients with heart failure receiving the drugs.1200,1250
In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 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.390,391,397,398,399,400 Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed.390,391 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.399,400 The ALLHAT investigators suggested that the observed differences in 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.399,400 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)
Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 Calcium-channel blockers may be particularly useful in the management of hypertension in black patients;195,204,212,224,227,230,281,285,397,398 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).501,504,1200 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses in Amlodipine 24:28.08.)
For additional information on the role of calcium-channel blockers in the management of hypertension, see Uses: Hypertension, in Amlodipine 24:28.08. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.
Hypertrophic Cardiomyopathy
Verapamil has been used as adjunctive therapy in the management of hypertrophic cardiomyopathy†.266,267,268,269,270,271,272,273,274,275,276,277,278,279,280,297 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 obstruction266,267,269,272,273,275,277,278,280 and also may alleviate and suppress concomitant supraventricular tachyarrhythmias.266,280 Verapamil therapy also has produced clinical improvement in patients without evidence of outflow obstruction.266,273,275,278 The drug can reduce the outflow tract gradient in patients with obstruction266,271,273,275,278 and enhance left ventricular diastolic filling (e.g., rate)268,271,272,273,274,297 and relaxation;266,268,271,274,297 the drug also appears to reduce regional systolic and diastolic asynchrony.274 In addition, limited evidence suggests that verapamil may limit the extent of ischemic myocardial changes in some patients with hypertrophic cardiomyopathy;268,269 however, the drug may not alter the underlying hypertrophic process,270,273,278,297 which apparently can progress slowly despite clinical and cardiac functional improvements induced by the drug270 and evidence of an increase in the number of calcium-channel blocker receptors (1,4-dihydropyridine receptors) in the myocardium of patients with this condition.298
While clinical improvement frequently occurs in patients with hypertrophic cardiomyopathy treated with verapamil,266,272,273,275 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.267,278 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.267 The clinical importance of such changes is not known,278 but some evidence suggests that decreases in LVPW thickness in patients with hypertrophic cardiomyopathy actually may result in left ventricular systolic dysfunction.299
Despite evidence of a lack of substantial effect on the underlying hypertrophic process,266,267,270,273,278,298 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.266,272,273,274,275,280,297 While the role of chronic drug therapy in asymptomatic patients with hypertrophic cardiomyopathy remains controversial,266,268,298 verapamil has improved reversible perfusion defects and exercise capacity in such patients,268 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.266
Verapamil appears to be more effective than propranolol as adjunctive therapy in the management of hypertrophic cardiomyopathy†266,273,275,276,277,278 and often is effective and can delay the need for surgery in patients who fail to respond to β-adrenergic blocker therapy.266,273,278 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.266 In another comparative study, clinical and hemodynamic improvement was greater with verapamil than with propranolol.275 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.266
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.275,277,297 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),153,266,273,278 paroxysmal nocturnal dyspnea or orthopnea,153,278 or clinically important SA nodal or AV junctional conduction abnormalities (unless a functional artificial ventricular pacemaker is in place).153,266,273,278
Acute Myocardial Infarction
Calcium-channel blockers have been used in the early treatment and secondary prevention of acute MI†; although these drugs are effective anti-ischemic agents, they have not demonstrated mortality benefits and therefore are generally used as an alternative to β-blockers.266,527,1100 A review of 28 randomized controlled studies involving 19,000 patients found no benefit with regard to infarct size, rate of reinfarction, or death when calcium-channel blockers were used during the acute or convalescent phase of ST-segment-elevation MI (STEMI).348,527 Although some studies demonstrated a reduced risk of reinfarction when verapamil or diltiazem was administered after MI in patients without left ventricular dysfunction, other studies have not confirmed this finding.1100 Calcium-channel blockers generally are used for their anti-ischemic and blood pressure-reducing properties in the MI setting, and only when β-blockers (which have been shown to reduce mortality after MI) are ineffective, not tolerated, or contraindicated; because the nondihydropyridine calcium-channel blockers (verapamil and diltiazem) can cause substantial negative inotropic effects, their use should be limited to patients without left ventricular dysfunction.527,702,1100
Current expert guidelines state that a calcium-channel blocker may be used to relieve ischemic symptoms, lower blood pressure, or control rapid ventricular response associated with atrial fibrillation in patients with STEMI who are intolerant to β-blockers.527 A nondihydropyridine calcium-channel blocker (e.g., verapamil or diltiazem) may be used as an alternative to β-blockers for relief of ongoing or recurring ischemia when β-blocker therapy is inadequate, not tolerated, or contraindicated in patients with non-ST-segment-elevation MI (NSTEMI) who do not have clinically important left ventricular dysfunction, increased risk of cardiogenic shock, or AV block.1100 The use of immediate-release nifedipine is generally contraindicated because of the potential for hypotension and reflex sympathetic activation.527,1100
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.139,145,146,147,148,149,150,151,152
Verapamil shares the toxic potentials of the calcium-channel blockers, 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.278 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.108 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 (MI) 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.306 Morbid dreams (paroniria) also have been reported in several other patients receiving the drug.307
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.248,249
Precautions and Contraindications
Some findings concerning possible risks of calcium-channel blockers have raised concerns about the safety and efficacy of these agents (mainly conventional [short-acting] preparations of nifedipine).322,323,324,326,327,328,329,330,331,332,333,334,335,336,337,338,339,340,341,342,343,344,345,346,348,359 (See Cautions, in Nifedipine 24:28.08.) 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.391,394 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)
Verapamil shares the toxic potentials of other nondihydropyridine calcium-channel blockers, 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.
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,130 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 of wide-complex ventricular tachycardia 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.207 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.382 However, severe adverse cardiovascular effects (e.g., refractory hypotension, cardiac arrest) have occurred rarely following IV administration of verapamil in neonates and infants.382 Therefore, the manufacturer states that IV verapamil should be used with caution in neonates and infants.382 However, some experts state that IV verapamil should not be used in infants. 381 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).381 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, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.
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,117,118,131,207 but the drug has increased human sperm motility in vitro.131
Lactation
Verapamil is distributed into milk.103,122,123,124 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.
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.
Beta-Adrenergic Blocking Agents
Concomitant use of nondihydropyridine calcium-channel blockers (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.356,357 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 (MI). 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 blocker mibefradil, principally in geriatric patients and in association with concomitant β-adrenergic blocker therapy.355,356 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),207,242,243 which was associated with a wandering atrial pacemaker in one patient,207,242 and transient asystole243 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.243 Verapamil should be used with extreme caution in patients receiving ophthalmic timolol;243 when therapy with a calcium-channel blocker 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.242,243
Verapamil may substantially increase the oral bioavailability of metoprolol, a lipophilic drug.117,118,141,142,143,207 Area under the plasma metoprolol concentration-time curve has increased up to 300% following initiation of verapamil therapy.141,142 Verapamil appears to increase oral bioavailability of metoprolol by decreasing its hepatic clearance, although the exact mechanism(s) has not been elucidated.141,142 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.117,118,141,142,143,207,317,318 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.141,142 If verapamil and metoprolol are used concomitantly, dosage of metoprolol should be adjusted carefully and the patient monitored closely.142 Verapamil also may decrease oral clearance of propranolol; minimal increases in plasma propranolol concentrations have been reported in some individuals receiving verapamil concomitantly.314,316,317
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).207,244 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.140 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.117,118,153,207 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.154 There is in vitro evidence that verapamil and quinidine have additive adrenergic-blocking activity at α1- and α2-receptors.154 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.117,118,155,207 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 dosa an increase in quinidine dosage was subsequently necessary when verapamil was discontinued after 5 months of combined therapy.155
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.104,105,106 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.104,105,106,207 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.104,105 The ratio of plasma carbamazepine 10,11-epoxide to unchanged drug decreased during verapamil therapy but returned toward pretreatment levels following discontinuance of verapamil.104 Limited experience suggests that a similar interaction may also occur when diltiazem, but not nifedipine, is administered concomitantly with carbamazepine.105,106,107 It appears that verapamil104,105,106 and possibly diltiazem106,107 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.104,105 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.104,105 If verapamil is discontinued, dosage of carbamazepine should be increased to avoid loss of seizure control.104,105
Rifampin
Rifampin may substantially reduce the oral bioavailability of verapamil.117,118,134,135,136,137,138,207 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.135 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.135 Arrhythmias were subsequently controlled at a lower verapamil dosage.135 It appears that rifampin may decrease oral bioavailability of verapamil by increasing first-pass metabolism via induction of hepatic microsomal enzymes.134,135,137,138 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;134,135,136,137,138 the effects of this interaction may persist for several days or longer following discontinuance of rifampin.135,137
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 verapamil109,110,111,112,113,114,117,118,207 and on bioavailability of oral verapamil109,110,111,112,113 have been reported. Studies to date have determined the effects of cimetidine on single IV or oral doses of verapamil109,110,111,112,113,114 and may not reflect the effects during multiple-dose verapamil therapy.109,110 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).109,110
Lithium
Serum lithium concentrations may decrease, increase, or remain unchanged during concomitant use of verapamil.117,118,132,133,207,241,362 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.132 Serum lithium concentrations also decreased in another patient and urinary excretion of the cation increased.132 Although the mechanism of this interaction currently is not known,132,133 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.117,118,132,133,207,241,361
There is also some evidence that verapamil may potentiate the neurotoxic effects of lithium.118,139,207,361,362 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.139 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.139 Verapamil did not appear to affect the pharmacokinetics of lithium in this patient.139 The mechanism of this interaction is not known,139,144 but a similar interaction has been described in a patient receiving lithium and diltiazem concomitantly.144 Calcium-channel blockers appear to share some of the neuropharmacologic effects of lithium,139,144,145,146,147,148,149,150 and combined therapy with the drugs may potentiate neurotoxicity.139,144 Pending further accumulation of data, verapamil and possibly other calcium-channel blockers should be used concomitantly with lithium cautiously.139,144
Flecainide
Experience with combined use of verapamil and flecainide is limited.117,118,292,293 In a small number of healthy individuals, concomitant administration of verapamil and flecainide showed possible additive effects on myocardial contractility.117,118,241 Because flecainide also has a negative inotropic effect and decreases AV nodal conduction,117,118,292,293 the manufacturer of flecainide cautions that flecainide and verapamil not be used concomitantly unless the potential benefits are considered to outweigh the risk.292,293
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.117,310,311,312,313 Patients receiving theophylline should be closely monitored for signs of theophylline toxicity when verapamil is administered concomitantly;312,313 serum theophylline concentrations should be monitored and dosage of the bronchodilator reduced if indicated.312,313
Alcohol
Verapamil may increase blood alcohol concentrations and prolong its effects.117,118,362,385 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 (AUC0-12) increased by 30%.385
Other Drugs
Verapamil can produce marked increases in blood cyclosporine concentrations.117,118,294,295,296 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.294,296
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 blocker 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,207,302,303,305 possibly via induction of hepatic cytochrome P-450 microsomal metabolism.303,304 Combined therapy with the drugs may decrease oral bioavailability of verapamil secondary to increased first-pass metabolism in the liver.305 The possibility that verapamil dosage may need to be adjusted following initiation or discontinuance of barbiturate therapy should be considered.305
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.
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