hould be part of comprehensive cardiovascular risk management, including, as appropriate, lipid control, diabetes management, antithrombotic therapy, smoking cessation, exercise, and limited sodium intake. many patients will require more than one drug to achieve blood pressure goals. for specific advice on goals and management, see published guidelines, such as those of the national high blood pressure education program's joint national committee on prevention, detection, evaluation, and treatment of high blood pressure (jnc). numerous antihypertensive drugs, from a variety of pharmacologic classes and with different mechanisms of action, have been shown in randomized controlled trials to reduce cardiovascular morbidity and mortality, and it can be concluded that it is blood pressure reduction, and not some other pharmacologic property of the drugs, that is largely responsible for those benefits. the largest and most consistent cardiovascular outcome benefit has been a reduction in the risk of stroke, but reductions in myocardial infarction and cardiovascular mortality also have been seen regularly. elevated systolic or diastolic pressure causes increased cardiovascular risk, and the absolute risk increase per mmhg is greater at higher blood pressures, so that even modest reductions of severe hypertension can provide substantial benefit. relative risk reduction from blood pressure reduction is similar across populations with varying absolute risk, so the absolute benefit is greater in patients who are at higher risk independent of their hypertension (for example, patients with diabetes or hyperlipidemia), and such patients would be expected to benefit from more aggressive treatment to a lower blood pressure goal. some antihypertensive drugs have smaller blood pressure effects (as monotherapy) in black patients, and many antihypertensive drugs have additional approved indications and effects (e.g., on angina, heart failure, or diabetic kidney disease). these considerations may guide selection of therapy.

which may result in dizziness or symptomatic hypotension. the incidence of hypotension observed in 4,954 patients enrolled in clinical trials was 2.5%. in hypertensive patients, decreases in blood pressure below normal are unusual. tilt-table testing (60 degrees) was not able to induce orthostatic hypotension. elevated liver enzymes: elevations of transaminases with and without concomitant elevations in alkaline phosphatase and bilirubin have been reported. such elevations have sometimes been transient and may disappear even with continued verapamil treatment. several cases of hepatocellular injury related to verapamil have been proven by rechallenge; half of these had clinical symptoms (malaise, fever, and/or right upper quadrant pain), in addition to elevation of sgot, sgpt, and alkaline phosphatase. periodic monitoring of liver function in patients receiving verapamil is therefore prudent. accessory bypass tract (wolff-parkinson-white or lown-ganong-levine): some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory av pathway have developed increased antegrade conduction across the accessory pathway bypassing the av node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated ( see contraindications ). treatment is usually dc-cardioversion. cardioversion has been used safely and effectively after oral verapamil hydrochloride. atrioventricular block: the effect of verapamil on av conduction and the sa node may cause asymptomatic first-degree av block and transient bradycardia, sometimes accompanied by nodal escape rhythms. pr-interval prolongation is correlated with verapamil plasma concentrations especially during the early titration phase of therapy. higher degrees of av block, however, were infrequently (0.8%) observed. marked first-degree block or progressive development to second-or third-degree av block requires a reduction in dosage or, in rare instances, discontinuation of verapamil hcl and institution of appropriate therapy, depending on the clinical situation. patients with hypertrophic cardiomyopathy (ihss): in 120 patients with hypertrophic cardiomyopathy (most of them refractory or intolerant to propranolol) who received therapy with verapamil at doses up to 720 mg/day, a variety of serious adverse effects were seen. three patients died in pulmonary edema; all had severe left ventricular outflow obstruction and a past history of left ventricular dysfunction. eight other patients had pulmonary edema and/or severe hypotension; abnormally high (greater than 20 mm hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. concomitant administration of quinidine ( see precautions , drug interactions ) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). sinus bradycardia occurred in 11% of the patients, second-degree av block in 4%, and sinus arrest in 2%. it must be appreciated that this group of patients had a serious disease with a high mortality rate. most adverse effects responded well to dose reduction, and only rarely did verapamil use have to be discontinued.

e for prophylaxis of psvt (non-digitalized patients) ranges from 240 to 480 mg/day in divided (t.i.d. or q.i.d.) doses. in general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy. essential hypertension: dose should be individualized by titration. the usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/ day). daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. the antihypertensive effects of verapamil hydrochloride are evident within the first week of therapy. upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval.

ontrol of ventricular response in digitalized patients who had atrial fibrillation or flutter, ventricular rates below 50 at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. the following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. digestive system : diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. hemic and lymphatic: ecchymosis or bruising. nervous system: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms. skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, stevens-johnson syndrome, erythema multiforme. special senses: blurred vision, tinnitus. urogenital: gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence. treatment of acute cardiovascular adverse reactions: the frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. whenever severe hypotension or complete av block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately; e.g., intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol hcl (all in the usual doses), or calcium gluconate (10% solution). in patients with hypertrophic cardiomyopathy (ihss), alphaadrenergic agents (phenylephrine hcl, metaraminol bitartrate, or methoxamine hcl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. if further support is necessary, dopamine hcl or dobutamine hcl may be administered. actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. to report suspected adverse reactions, contact avet pharmaceuticals inc. at 1-866-901-drug (3784) or fda at 1-800-fda-1088 or www.fda.gov/medwatch.

na at rest. whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate-pressure product, a widely accepted measure of oxygen utilization. this suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. reduction of oxygen utilization: verapamil hydrochloride regularly reduces the total peripheral resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. this unloading of the heart reduces myocardial energy consumption and oxygen requirements and probably accounts for the effectiveness of verapamil hydrochloride in chronic stable effort angina. arrhythmia: electrical activity through the av node depends, to a significant degree, upon calcium influx through the slow channel. by decreasing the influx of calcium, verapamil hydrochloride prolongs the effective refractory period within the av node and slows av conduction in a rate-related manner. this property accounts for the ability of verapamil hydrochloride to slow the ventricular rate in patients with chronic atrial flutter or atrial fibrillation. normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil hydrochloride may interfere with sinus-node impulse generation and may induce sinus arrest or sinoatrial block. atrioventricular block can occur in patients without preexisting conduction defects ( see warnings ). verapamil hydrochloride decreases the frequency of episodes of paroxysmal supraventricular tachycardia. verapamil hydrochloride does not alter the normal atrial action potential or intraventricular conduction time, but in depressed atrial fibers it decreases amplitude, velocity of depolarization, and conduction velocity. verapamil hydrochloride may shorten the antegrade effective refractory period of the accessory bypass tract. acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory av pathway following administration of verapamil ( see warnings ). verapamil hydrochloride has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. it is not known whether this action is important at the doses used in man. essential hypertension: verapamil hydrochloride exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). during isometric or dynamic exercise, verapamil hydrochloride does not alter systolic cardiac function in patients with normal ventricular function. verapamil hydrochloride does not alter total serum calcium levels. however, one report suggested that calcium levels above the normal range may alter the therapeutic effect of verapamil hydrochloride. pharmacokinetics and metabolism: more than 90% of the orally administered dose of verapamil hydrochloride is absorbed. because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. peak plasma concentrations are reached between 1 and 2 hours after oral administration. chronic oral administration of 120 mg of verapamil hcl every 6 hours resulted in plasma levels of verapamil ranging from 125 to 400 ng/ml, with higher values reported occasionally. a nonlinear correlation between the verapamil dose administered and verapamil plasma levels does exist. no relationship has been established between the plasma concentration of verapamil and a reduction in blood pressure. in early dose titration with verapamil, a relationship exists between verapamil plasma concentration and prolongation of the pr interval. however, during chronic administration this relationship may disappear. the mean elimination half-life in single-dose studies ranged from 2.8 to 7.4 hours. in these same studies, after repetitive dosing, the half-life increased to a range from 4.5 to 12.0 hours (after less than 10 consecutive doses given 6 hours apart). half-life of verapamil may increase during titration. aging may affect the pharmacokinetics of verapamil. elimination half-life may be prolonged in the elderly. in healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver. twelve metabolites have been identified in plasma; all except norverapamil are present in trace amounts only. norverapamil can reach steady-state plasma concentrations approximately equal to those of verapamil itself. the cardiovascular activity of norverapamil appears to be approximately 20% that of verapamil. approximately 70% of an administered dose is excreted as metabolites in the urine and 16% or more in the feces within 5 days. about 3% to 4% is excreted in the urine as unchanged drug. approximately 90% is bound to plasma proteins. in patients with hepatic insufficiency, metabolism is delayed and elimination half-life prolonged up to 14 to 16 hours ( see precautions ); the volume of distribution is increased and plasma clearance reduced to about 30% of normal. verapamil clearance values suggest that patients with liver dysfunction may attain therapeutic verapamil plasma concentrations with one third of the oral daily dose required for patients with normal liver function. after four weeks of oral dosing (120 mg q.i.d.), verapamil and norverapamil levels were noted in the cerebrospinal fluid with estimated partition coefficient of 0.06 for verapamil and 0.04 for norverapamil. hemodynamics and myocardial metabolism: verapamil hydrochloride reduces afterload and myocardial contractility. improved left ventricular diastolic function in patients with idiopathic hypertrophic subaortic stenosis (ihss) and those with coronary heart disease has also been observed with verapamil hydrochloride therapy. in most patients, including those with organic cardiac disease, the negative inotropic action of verapamil hydrochloride is countered by reduction of afterload, and cardiac index is usually not reduced. however, in patients with severe left ventricular dysfunction (e.g., pulmonary wedge pressure above 20 mm hg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see precautions , drug interactions ). pulmonary function: verapamil hydrochloride does not induce bronchoconstriction and, hence, does not impair ventilatory function.