of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. limit the dose of simvastatin in patients on verapamil to 10 mg daily. limit the daily dose of lovastatin to 40 mg. lower starting and maintenance doses of other cyp3a4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs. beta blockers concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. the combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. however, there have been reports of excess bradycardia and av block, including complete heart block, when the combination has been used for the treatment of hypertension. for hypertensive patients, the risk of combined therapy may outweigh the potential benefits. the combination should be used only with caution and close monitoring. asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. a decrease in metoprolol clearance has been reported when verapamil and metoprolol were administered together. a similar effect has not been observed when verapamil and atenolol are given together. clonidine sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. monitor heart rate in patients receiving concomitant verapamil and clonidine. digitalis consider reducing digoxin dose when verapamil and digoxin are to be given together. monitor digoxin level periodically during therapy. chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. in patients with hepatic cirrhosis the influence of verapamil on digoxin pharmacokinetics is magnified. verapamil may reduce total body clearance and extrarenal clearance of digoxin by 27% and 29%, respectively. if digoxin toxicity is suspected, suspend or discontinue digoxin therapy. in previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients. antihypertensive agents verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. patients receiving these combinations should be appropriately monitored. concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in reduction in blood pressure that is excessive in some patients. such an effect was observed in one study following the concomitant administration of verapamil and prazosin. antiarrhythmic agents disopyramide: until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. flecainide: a study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, av conduction, and repolarization. concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. quinidine: in a small number of patients with hypertrophic cardiomyopathy (ihss), concomitant use of verapamil and quinidine resulted in significant hypotension. until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. the electrophysiological effects of quinidine and verapamil on av conduction were studied in 8 patients. verapamil significantly counteracted the effects of quinidine on av conduction. there has been a report of increased quinidine levels during verapamil therapy. nitrates: verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. the pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. alcohol: verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (see clinical pharmacology - pharmacokinetics and metabolism .)

pertensive 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.

ult 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 in the face of 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 elevations 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 flutter or atrial fibrillation 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. atrioventricular block the effect of verapamil on av conduction and the sa node may lead to 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 upon 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 (over 20 mm hg) capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. concomitant administration of quinidine (see drug interactions ) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). sinus bradycardia occurred in 11% of the patients, second-degree 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 have to be discontinued.

th attenuated neuromuscular transmission. use in patients with impaired renal function about 70% of an administered dose of verapamil is excreted as metabolites in the urine. until further data are available, verapamil should be administered cautiously to patients with impaired renal function. these patients should be carefully monitored for abnormal prolongation of the pr interval or other signs of overdosage. (see overdosage . )

erapamil hydrochloride sustained-release capsules are for once-a-day administration. when switching from immediate-release verapamil to verapamil hydrochloride sustained-release capsules, the same total daily dose of verapamil hydrochloride sustained-release capsules can be used. as with immediate-release verapamil, dosages of verapamil hydrochloride sustained-release capsules should be individualized and titration may be needed in some patients. sprinkling the capsule contents on food verapamil hydrochloride sustained-release capsules may also be administered by carefully opening the capsule and sprinkling the pellets on a spoonful of applesauce. the applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the pellets. the applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. any pellet/applesauce mixture should be used immediately and not stored for future use. subdividing the contents of a verapamil hydrochloride sustained-release capsule is not recommended.

2.5% edema 1.9% headache 2.2% rash 1.2% chf/pulmonary edema 1.8% fatigue 1.7% bradycardia (hr<50/min) 1.4% av block-total 1°, 2°, 3° 1.2% 2° and 3° 0.8% flushing 0.6% elevated liver enzymes (see warnings ) in clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rate below 50/min 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, extrapyramidal symptoms, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence. respiratory: dyspnea. skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, stevens-johnson syndrome, erythema multiforme. special senses: blurred vision, tinnitus. urogenital: gynecomastia, impotence, increased urination, spotty menstruation. treatment of acute cardiovascular adverse reactions the frequency of cardiovascular adverse reactions which 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 isoproterenol hcl, levarterenol bitartrate, atropine (all in the usual doses), or calcium gluconate (10% solution). in patients with hypertrophic cardiomyopathy (ihss), alpha-adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol and levarterenol should be avoided. if further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. actual treatment and dosage should depend on the severity and the clinical situation and the judgment and experience of the treating physician. to report suspected adverse events, contact teva at 1-888-838-2872 or fda at 1-800-fda-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

of multiple doses of 10 mg of verapamil with 80 mg simvastatin resulted in exposure to simvastatin 2.5-fold that following simvastatin alone. limit the dose of simvastatin in patients on verapamil to 10 mg daily. limit the daily dose of lovastatin to 40 mg. lower starting and maintenance doses of other cyp3a4 substrates (e.g., atorvastatin) may be required as verapamil may increase the plasma concentration of these drugs. beta blockers concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. the combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. however, there have been reports of excess bradycardia and av block, including complete heart block, when the combination has been used for the treatment of hypertension. for hypertensive patients, the risk of combined therapy may outweigh the potential benefits. the combination should be used only with caution and close monitoring. asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. a decrease in metoprolol clearance has been reported when verapamil and metoprolol were administered together. a similar effect has not been observed when verapamil and atenolol are given together. clonidine sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. monitor heart rate in patients receiving concomitant verapamil and clonidine. digitalis consider reducing digoxin dose when verapamil and digoxin are to be given together. monitor digoxin level periodically during therapy. chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. in patients with hepatic cirrhosis the influence of verapamil on digoxin pharmacokinetics is magnified. verapamil may reduce total body clearance and extrarenal clearance of digoxin by 27% and 29%, respectively. if digoxin toxicity is suspected, suspend or discontinue digoxin therapy. in previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients. antihypertensive agents verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. patients receiving these combinations should be appropriately monitored. concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in reduction in blood pressure that is excessive in some patients. such an effect was observed in one study following the concomitant administration of verapamil and prazosin. antiarrhythmic agents disopyramide: until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. flecainide: a study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, av conduction, and repolarization. concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. quinidine: in a small number of patients with hypertrophic cardiomyopathy (ihss), concomitant use of verapamil and quinidine resulted in significant hypotension. until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. the electrophysiological effects of quinidine and verapamil on av conduction were studied in 8 patients. verapamil significantly counteracted the effects of quinidine on av conduction. there has been a report of increased quinidine levels during verapamil therapy. nitrates: verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. the pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. alcohol: verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (see clinical pharmacology - pharmacokinetics and metabolism .)

e 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 hcl 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. mechanism of action essential hypertension verapamil hcl exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/minute is uncommon). verapamil hcl regularly reduces arterial pressure at rest and at a given level of exercise by dilating peripheral arterioles and reducing the total peripheral resistance (afterload) against which the heart works. pharmacokinetics and metabolism with the immediate release formulations, more than 90% of the orally administered dose is absorbed, and peak plasma concentrations of verapamil are observed 1 to 2 hours after dosing. because of rapid biotransformation of verapamil during its first pass through the portal circulation, the absolute bioavailability ranges from 20% to 35%. chronic oral administration of the highest recommended dose (120 mg every 6 hours) resulted in plasma verapamil levels ranging from 125 to 400 ng/ml with higher values reported occasionally. a nonlinear correlation between the verapamil hcl dose administered and verapamil plasma levels does exist. during initial dose titration with verapamil a relationship exists between verapamil plasma concentrations and the prolongation of the pr interval. however, during chronic administration this relationship may disappear. the quantitative relationship between plasma verapamil concentrations and blood pressure reduction has not been fully characterized. in a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of verapamil hydrochloride sustained-release capsules 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24 hour post-dose concentrations were approximately 30% higher. at a total daily dose of 240 mg, verapamil hydrochloride sustained-release capsules was shown to have a similar extent of verapamil bioavailability based on the auc-24 as that obtained with the conventional immediate-release tablets. in this same study verapamil hydrochloride sustained-release capsules doses of 120 mg, 240 mg and 360 mg once daily were compared after multiple doses. the ratios of the verapamil and norverapamil aucs for the verapamil hydrochloride sustained-release capsules 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng∙hr/ml):3 (1660 ng∙hr/ml):5 (2729 ng∙hr/ml) and 1 (621 ng∙hr/ml):3 (1614 ng∙hr/ml):4 (2535 ng∙hr/ml) respectively, indicating that the auc increased non-proportionately with increasing doses. food does not affect the extent or rate of the absorption of verapamil from the controlled release verapamil hydrochloride sustained-release capsule. the verapamil hydrochloride sustained-release capsules 240 mg capsule when administered with food had a c max of 77 ng/ml which occurred 9.0 hours after dosing, and an auc(0-inf) of 1387 ng∙hr/ml. verapamil hydrochloride sustained-release capsules 240 mg under fasting conditions had a c max of 77 ng/ml which occurred 9.8 hours after dosing, and an auc(0-inf) of 1541 ng∙hr/ml. the bioequivalence of verapamil hydrochloride sustained-release capsule 240 mg, administered as the pellets sprinkled on applesauce and as the intact capsule, was demonstrated in a single-dose, cross-over study in 32 healthy adults. comparative ratios (sprinkled/intact) of verapamil were 0.95, 1.02, and 1.01 for c max , t max , and auc(0-inf) respectively. when the contents of the verapamil hydrochloride sustained-release capsule were administered by sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the same dose when administered as an intact capsule. similar results were observed with norverapamil. the time to reach maximum verapamil concentrations (t max ) with verapamil hydrochloride sustained-release capsules has been found to be approximately 7-9 hours in each of the single dose (fasting), single dose (fed), the multiple dose (steady state) studies and dose proportionality pharmacokinetic studies. similarly the apparent half-life (t 1/2 ) has been found to be approximately 12 hours independent of dose. aging may affect the pharmacokinetics of verapamil. elimination half-life may be prolonged in the elderly. in healthy man, orally administered verapamil hcl 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 biologic activity of norverapamil appears to be approximately 20% that of verapamil. approximately 70% of an administered dose of verapamil hcl 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. in 10 healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg), resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg/dl) compared with placebo. (see precautions-drug interactions . ) the area under the blood ethanol concentration versus time curve (auc over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg∙hr/dl). verapamil aucs were positively correlated (r = 0.71) to increased ethanol blood auc values. geriatric use: the pharmacokinetics of verapamil gits were studied after 5 consecutive nights of dosing 180 mg in 30 healthy young (19-43 years) versus 30 healthy elderly (65-80 years) male and female subjects. older subjects had significantly higher mean verapamil c max , c min , and auc (0-24h) compared to younger subjects. older subjects had mean aucs that were approximately 1.7-2.0 times higher than those of younger subjects as well as a longer average verapamil t 1/2 (approximately 20 hr vs 13 hr). hemodynamics and myocardial metabolism verapamil hcl reduces afterload and myocardial contractility. improved left ventricular diastolic function in patients with ihss and those with coronary heart disease has also been observed with verapamil hcl therapy. in most patients, including those with organic cardiac disease, the negative inotropic action of verapamil hcl is countered by reduction of afterload and cardiac index is usually not reduced. in patients with severe left ventricular dysfunction however, (e.g., pulmonary wedge pressure above 20 mm hg or ejection fraction lower than 30%), or in patients on beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur. (see drug interactions . ) pulmonary function verapamil hcl does not induce broncho-constriction and hence, does not impair ventilatory function.

n fully characterized. in a multiple dose pharmacokinetic study, peak concentrations for a single daily dose of verapamil hydrochloride sustained-release capsules 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24 hour post-dose concentrations were approximately 30% higher. at a total daily dose of 240 mg, verapamil hydrochloride sustained-release capsules was shown to have a similar extent of verapamil bioavailability based on the auc-24 as that obtained with the conventional immediate-release tablets. in this same study verapamil hydrochloride sustained-release capsules doses of 120 mg, 240 mg and 360 mg once daily were compared after multiple doses. the ratios of the verapamil and norverapamil aucs for the verapamil hydrochloride sustained-release capsules 120 mg, 240 mg and 360 mg once daily doses are 1 (565 ng∙hr/ml):3 (1660 ng∙hr/ml):5 (2729 ng∙hr/ml) and 1 (621 ng∙hr/ml):3 (1614 ng∙hr/ml):4 (2535 ng∙hr/ml) respectively, indicating that the auc increased non-proportionately with increasing doses. food does not affect the extent or rate of the absorption of verapamil from the controlled release verapamil hydrochloride sustained-release capsule. the verapamil hydrochloride sustained-release capsules 240 mg capsule when administered with food had a c max of 77 ng/ml which occurred 9.0 hours after dosing, and an auc(0-inf) of 1387 ng∙hr/ml. verapamil hydrochloride sustained-release capsules 240 mg under fasting conditions had a c max of 77 ng/ml which occurred 9.8 hours after dosing, and an auc(0-inf) of 1541 ng∙hr/ml. the bioequivalence of verapamil hydrochloride sustained-release capsule 240 mg, administered as the pellets sprinkled on applesauce and as the intact capsule, was demonstrated in a single-dose, cross-over study in 32 healthy adults. comparative ratios (sprinkled/intact) of verapamil were 0.95, 1.02, and 1.01 for c max , t max , and auc(0-inf) respectively. when the contents of the verapamil hydrochloride sustained-release capsule were administered by sprinkling onto one tablespoonful of applesauce, the rate and extent of verapamil absorption were found to be bioequivalent to the same dose when administered as an intact capsule. similar results were observed with norverapamil. the time to reach maximum verapamil concentrations (t max ) with verapamil hydrochloride sustained-release capsules has been found to be approximately 7-9 hours in each of the single dose (fasting), single dose (fed), the multiple dose (steady state) studies and dose proportionality pharmacokinetic studies. similarly the apparent half-life (t 1/2 ) has been found to be approximately 12 hours independent of dose. aging may affect the pharmacokinetics of verapamil. elimination half-life may be prolonged in the elderly. in healthy man, orally administered verapamil hcl 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 biologic activity of norverapamil appears to be approximately 20% that of verapamil. approximately 70% of an administered dose of verapamil hcl 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. in 10 healthy males, administration of oral verapamil (80 mg every 8 hours for 6 days) and a single oral dose of ethanol (0.8 g/kg), resulted in a 17% increase in mean peak ethanol concentrations (106.45 ± 21.40 to 124.23 ± 24.74 mg/dl) compared with placebo. (see precautions-drug interactions . ) the area under the blood ethanol concentration versus time curve (auc over 12 hours) increased by 30% (365.67 ± 93.52 to 475.07 ± 97.24 mg∙hr/dl). verapamil aucs were positively correlated (r = 0.71) to increased ethanol blood auc values. geriatric use: the pharmacokinetics of verapamil gits were studied after 5 consecutive nights of dosing 180 mg in 30 healthy young (19-43 years) versus 30 healthy elderly (65-80 years) male and female subjects. older subjects had significantly higher mean verapamil c max , c min , and auc (0-24h) compared to younger subjects. older subjects had mean aucs that were approximately 1.7-2.0 times higher than those of younger subjects as well as a longer average verapamil t 1/2 (approximately 20 hr vs 13 hr).

rotect from moisture. dispense in tight, light-resistant container as defined in usp.