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CLINICAL PHARMACOLOGY Mechanism Of Action Verapamil is a calcium ion influx inhibitor (L-type calcium channel blocker or calcium channel antagonist). Verapamil exerts its pharmacologic effects by selectively inhibiting the transmembrane influx of ionic calcium into arterial smooth muscle as well as in conductile and contractile myocardial cells without altering serum calcium concentrations. Verapamil binding is voltage-dependent with affinity increasing as the vascular smooth muscle membrane potential is reduced. In addition, verapamil binding is frequency dependent and apparent affinity increases with increased frequency of depolarizing stimulus. The L-type calcium channel is an oligomeric structure consisting of five putative subunits designated alpha-1, alpha-2, beta, tau, and epsilon. Biochemical evidence points to separate binding sites for 1,4-dihydropyridines, phenylalkylamines, and the benzothiazepines (all located on the alpha-1 subunit). Although they share a similar mechanism of action, calcium channel blockers represent three heterogeneous categories of drugs with differing vascular-cardiac selectivity ratios. Pharmacodynamics Essential Hypertension Verapamil produces its antihypertensive effect by a combination of vascular and cardiac effects. It acts as a vasodilator with selectivity for the arterial portion of the peripheral vasculature. As a result the systemic vascular resistance is reduced and usually without orthostatic hypotension or reflex tachycardia. Bradycardia (rate less than 50 beats/min) is uncommon. During isometric or dynamic exercise verapamil does not alter systolic cardiac function in patients with normal ventricular function. Verapamil does not alter total serum calcium levels. However, one report has suggested that calcium levels above the normal range may alter the therapeutic effect of verapamil. Verapamil regularly reduces the total systemic resistance (afterload) against which the heart works both at rest and at a given level of exercise by dilating peripheral arterioles. Electrophysiologic Effects Electrical activity through the AV node depends, to a significant degree, upon the transmembrane influx of extracellular calcium through the L-type (slow) channel. By decreasing the influx of calcium, verapamil prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner. Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil 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 AND PRECAUTIONS]. Verapamil does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization, and conduction in depressed atrial fibers. Verapamil 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 AND PRECAUTIONS]. Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. Hemodynamics Verapamil reduces afterload and myocardial contractility. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by reduction of afterload and cardiac index remains unchanged. During isometric or dynamic exercise, verapamil does not alter systolic cardiac function in patients with normal ventricular function. 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 DRUG INTERACTIONS]. Pulmonary Function Verapamil does not induce bronchoconstriction and, hence, does not impair ventilatory function. Verapamil has been shown to have either a neutral or relaxant effect on bronchial smooth muscle. Pharmacokinetics Verapamil is administered as a racemic mixture of the R and S enantiomers. The systemic concentrations of R and S enantiomers, as well as overall bioavailability, are dependent upon the route of administration and the rate and extent of release from the dosage forms. Upon oral administration, there is rapid stereoselective biotransformation during the first pass of verapamil through the portal circulation. Absorption In a study in 5 subjects with oral immediate-release verapamil, the systemic bioavailability was from 33% to 65% for the R enantiomer and from 13% to 34% for the S enantiomer. Following oral administration of an immediately releasing formulation every 8 hours in 24 subjects, the relative systemic availability of the S enantiomer compared to the R enantiomer was approximately 13% following a single day's administration and approximately 18% following administration to steady-state. The degree of stereoselectivity of metabolism for Verelan PM was similar to that for the immediately releasing formulation. The R and S enantiomers have differing levels of pharmacologic activity. In studies in animals and humans, the S enantiomer has 8 to 20 times the activity of the R enantiomer in slowing AV conduction. In animal studies, the S enantiomer has 15 to 50 times the activity of the R enantiomer in reducing myocardial contractility in isolated blood-perfused dog papillary muscle, respectively, and twice the effect in reducing peripheral resistance. In isolated septal strip preparations from 5 patients, the S enantiomer was 8 times more potent than the R in reducing myocardial contractility. Dose escalation study data indicate that verapamil concentrations increase disproportionally to dose as measured by relative peak plasma concentrations (Cmax) or areas under the plasma concentration vs time curves (AUC). Consumption of a high fat meal just prior to dosing in the morning had no effect on the extent of absorption and a modest effect on the rate of absorption from Verelan PM. The rate of absorption was not affected by whether the volunteers were supine two hours after night-time dosing or non-supine for four hours following morning dosing. Administering Verelan PM in the morning increased the extent of absorption of verapamil and/or decreased the metabolism to norverapamil. When the contents of the Verelan PM 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. Distribution Although some evidence of lack of dose linearity was observed for Verelan PM, this non-linearity was enantiomer specific, with the R enantiomer showing the greatest degree of non-linearity. Table 3: Pharmacokinetic Characteristics of Verapamil Enantiomers After Administration of Escalating Doses of Verelan PM ISOMER 200 300 400 Dose Ratio 1 1.5 2 Relative Cmax R 1 1.89 2.34 S 1 1.88 2.5 Relative AUC R 1 1.67 2.34 S 1 1.35 2.20 Racemic verapamil is released from Verelan PM by diffusion following the gradual solubilization of the water soluble polymer. The rate of solubilization of the water soluble polymer produces a lag period in drug release for approximately 4-5 hours. The drug release phase is prolonged with the peak plasma concentration (Cmax) occurring approximately 11 hours after administration. Trough concentrations occur approximately 4 hours after bedtime dosing while the patient is sleeping. Steady-state pharmacokinetics were determined in healthy volunteers. Steady-state concentration is achieved by day 5 of dosing. In healthy volunteers, following administration of VerelanPM (200 mg per day), steady-state pharmacokinetics of the R and S enantiomers of verapamil is as follows: Mean Cmax of the R isomer was 77.8 ng/ml and 16.8 ng/ml for the S isomer; AUC (0-24h) of the R isomer was 1037 ng·h/ml and 195 ng·h/ml for the S isomer. In general, bioavailability of verapamil is higher and half life longer in older ( > 65 yrs) subjects. Lean body weight also affects its pharmacokinetics inversely. It was not possible to observe a gender difference in the clinical trials of Verelan PM due to the small sample size. However, there are conflicting data in the literature suggesting that verapamil clearance decreased with age in women to a greater degree than in men. Metabolism and Excretion Orally administered verapamil undergoes extensive metabolism in the liver. Verapamil is metabolized by O-demethylation (25%) and N-dealkylation (40%), and is subject to pre-systemic hepatic metabolism with elimination of up to 80% of the dose. The metabolism is mediated by hepatic cytochrome P450, and animal studies have implied that the monooxygenase is the specific isoenzyme of the P450 family. Thirteen metabolites have been identified in urine. Norverapamil enantiomers can reach steady-state plasma concentrations approximately equal to those of the enantiomers of the parent drug. For Verelan PM, the norverapamil R enantiomer reached steady-state plasma concentrations similar to the verapamil R enantiomer, but the norverapamil S enantiomer concentrations were approximately twice that of the verapamil S enantiomer concentrations. 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. R verapamil is 94% bound to plasma albumin, while S verapamil is 88% bound. In addition, R verapamil is 92% and S verapamil 86% bound to alpha-1 acid glycoprotein. In patients with hepatic insufficiency, metabolism of immediate-release verapamil is delayed and elimination half-life prolonged up to 14 to 16 hours because of the extensive hepatic metabolism [see Use In Specific Populations]. In addition, in these patients there is a reduced first pass effect, and verapamil is more bioavailable. 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 of immediate-release verapamil (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. 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 Cmax, Cmin 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 t½ (approximately 20 hr vs 13 hr). Animal Toxicology And/Or Pharmacology In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not in the rat. Development of cataracts due to verapamil has not been reported in man. Clinical Studies Verelan PM was evaluated in two placebo-controlled, parallel design, double-blind studies of patients with mild to moderate hypertension. In the clinical trials, 413 evaluable patients were randomized to either placebo, 100 mg, 200 mg, 300 mg, or 400 mg and treated for up to 8 weeks. Verelan PM or placebo was given once daily between 9 pm and 11 pm (nighttime) and blood pressure changes were measured with 36-hour ambulatory blood pressure monitoring (ABPM). The results of these studies demonstrate that Verelan PM, at 200, 300 and 400 mg, is a consistently and significantly more effective antihypertensive agent than placebo in reducing ambulatory blood pressures. Over this dose range, the placebo-subtracted net decreases in diastolic BP at trough (averaged over 6-10 pm) were dose-related, and ranged from 3.8 to 10.0 mm Hg after 8 weeks of therapy. Although Verelan PM 100 mg was not effective in reducing diastolic BP at trough when measured by ABPM, efficacy was demonstrated in reducing diastolic BP when measured manually at trough and peak and, from 6 am to 12 noon and over 24 hours when measured by ABPM [see DOSAGE AND ADMINISTRATION for titration schedule)]. There were no apparent treatment differences between patient subgroups of different age (older or younger than 65 years), sex and race. For severity of hypertension, “moderate” hypertensives (mean daytime diastolic BP 105 mm Hg and 114 mm Hg) appeared to respond better than “mild” hypertensives (mean daytime diastolic BP 90 mm Hg and 104 mm Hg). However, sample size for the subgroup comparisons were limited.

CLINICAL PHARMACOLOGY Verelan is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exerts its pharmacologic effects by modulating the influx of ionic calcium across the cell membrane of the arterial smooth muscle as well as in conductile and contractile myocardial cells. Normal sinus rhythm is usually not affected by verapamil HCl. However in patients with sick sinus syndrome, verapamil HCl 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 HCl does not alter the normal atrial action potential or intraventricular conduction time, but depresses amplitude, velocity of depolarization and conduction in depressed atrial fibers. Verapamil HCl may shorten the antegrade effective refractory period of accessory bypass tracts. 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 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 Verelan 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediaterelease tablets, and the 24 hour post-dose concentrations were approximately 30% higher. At a total daily dose of 240 mg, Verelan 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 Verelan 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 Verelan 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 Verelan capsule. The Verelan 240 mg capsule when administered with food had a Cmax of 77 ng/mL which occurred 9.0 hours after dosing, and an AUC(O-inf) of 1387 ng·hr/mL. Verelan 240 mg under fasting conditions had a Cmax of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(O-inf) of 1541 ng·hr/mL. The bioequivalence of Verelan 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 Cmax, Tmax, and AUC(O-inf) respectively. When the contents of the Verelan® 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 (Tmax) with Verelan 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 (t1/2) 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 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 (65-80years) male and female subjects. Older subjects had significantly higher mean verapamil Cmax, Cmin 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 (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 cardio-depressant 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. Animal Pharmacology And/Or Animal Toxicology In chronic animal toxicology studies verapamil caused lenticular and/or suture line changes at 30 mg/kg/day or greater and frank cataracts at 62.5 mg/kg/day or greater in the beagle dog but not the rat. Development of cataracts due to verapamil has not been reported in man.

CLINICAL PHARMACOLOGY Mechanism Of Action Verapamil inhibits the calcium ion (and possibly sodium ion) influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells. The antiarrhythmic effect of verapamil appears to be due to its effect on the slow channel in cells of the cardiac conduction system. The vasodilatory effect of verapamil appears to be due to its effect on blockade of calcium channels as well as α receptors. In the isolated rabbit heart, concentrations of verapamil that markedly affect SA nodal fibers or fibers in the upper and middle regions of the AV node have very little effect on fibers in the lower AV node (NH region) and no effect on atrial action potentials or His bundle fibers. Electrical activity in the SA and AV nodes depends, to a large degree, upon calcium influx through theslow channel. By inhibiting this influx, verapamil slows AV conduction and prolongs the effective refractory period within the AV node in a rate-related manner. This effect results in a reduction of the ventricular rate in patients with atrial flutter and/or atrial fibrillation and a rapid ventricular response. By interrupting reentry at the AV node, verapamil can restore normal sinus rhythm in patients withparoxysmal supraventricular tachycardias (PSVT), including PSVT associated with Wolff-Parkinson- White syndrome. Verapamil does not induce peripheral arterial spasm. Verapamil has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. Verapamil does not alter total serum calcium levels. Hemodynamics Verapamil reduces afterload and myocardial contractility. The commonly used intravenous doses of 5 to 10 mg verapamil hydrochloride produce transient, usually asymptomatic, reduction in normal systemic arterial pressure, systemic vascular resistance and contractility; left ventricular filling pressure is slightly increased. In most patients, including those with organic cardiac disease, the negative inotropic action of verapamil is countered by reduction of afterload, and cardiac index is usually not reduced. However, in patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Peak therapeutic effects occur within 3 to 5 minutes after a bolus injection. Pharmacokinetics Intravenously administered verapamil hydrochloride has been shown to be rapidly metabolized. Following intravenous infusion in man, verapamil is eliminated bi-exponentially, with a rapid early distribution phase (half-life about 4 minutes) and a slower terminal elimination phase (halflife 2 to 5 hours). In healthy men, orally administered verapamil hydrochloride undergoes extensive metabolism in the liver, with 12 metabolites having been identified, most in only trace amounts. The major metabolites have been identified as various N- and O-dealkylated products of verapamil. Approximately 70% of an administered dose is excreted in the urine and 16% more in the feces within 5 days. About 3% to 4% is excreted as unchanged drug. Aging may affect the pharmacokinetics of verapamil given to hypertensive patients. Elimination half-life may be prolonged in the elderly.

Find Lowest Prices on VERELAN PM (verapamil hydrochloride) Extended-release Capsules DESCRIPTION Verelan PM (verapamil hydrochloride) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verelan PM is available for oral administration as a 100 mg hard gelatin capsule (white opaque cap/amethyst body), a 200 mg hard gelatin capsule (amethyst opaque cap/amethyst body), and as a 300 mg hard gelatin capsule (lavender opaque cap/amethyst body). Verapamil is administered as a racemic mixture of the R and S enantiomers. The structural formulae of the verapamil HCl enantiomers are: C27H38N2O4•HCl M W. =491.07 Chemical name: Benzeneacetonitrile, -[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]- 3,4-dimethoxy- -(1methylethyl)-, monohydrochloride,(&plusn;)-. Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil HCl is not structurally related to other cardioactive drugs. In addition to verapamil HCl the Verelan PM capsule contains the following inactive ingredients: D&C Red #28, FD & C Blue #1, FD&C red #40, fumaric acid, gelatin, povidone, shellac, silicon dioxide, sodium lauryl sulfate, starch, sugar spheres, talc, and titanium dioxide. System Components and Performance Verelan PM uses the proprietary CODAS® (Chronotherapeutic Oral Drug Absorption System) technology, which is designed for bedtime dosing, incorporating a 4 to 5-hour delay in drug delivery. The controlled-onset delivery system results in a maximum plasma concentration (Cmax) of verapamil in the morning hours. These pellet filled capsules provide for extended-release of the drug in the gastrointestinal tract. The Verelan PM formulation has been designed to initiate the release of verapamil 4-5 hours after ingestion. This delay is introduced by the level of non-enteric release-controlling polymer applied to drug loaded beads. The release-controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer coated beads, the water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the drug. The rate of release is essentially independent of pH, posture and food. Multiparticulate systems such as Verelan PM have been shown to be independent of gastrointestinal motility.

Find Lowest Prices on Verelan® (verapamil hydrochloride) Capsules DESCRIPTION Verelan® (verapamil hydrochloride capsules) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verelan is available for oral administration as a 360 mg hard gelatin capsule (lavender cap/yellow body), a 240 mg hard gelatin capsule (dark blue cap/yellow body), a 180 mg hard gelatin capsule (light grey cap/yellow body), and a 120 mg hard gelatin capsule (yellow cap/yellow body). These pellet filled capsules provide a sustained-release of the drug in the gastrointestinal tract. The structural formula of verapamil HCl is given below: C27H38N2O4·HCl M.W. 4 91.07 Chemical name: Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)-ethyl]methylamino]propyl]-3,4- dimethoxy-α-(1-methylethyl), monohydrochloride. Verapamil HCl is an almost white, crystalline powder, practically free of odor, with a bitter taste. It is soluble in water, chloroform and methanol. Verapamil HCl is not structurally related to other cardioactive drugs. In addition to verapamil HCl the Verelan capsule contains the following inactive ingredients: fumaric acid, talc, sugar spheres, povidone, shellac, gelatin, FD&C red #40, yellow iron oxide, titanium dioxide, methylparaben, propylparaben, silicon dioxide, and sodium lauryl sulfate. In addition, the Verelan 240 mg and 360 mg capsules contain FD&C blue #1 and D&C red #28; and the Verelan 180 mg capsule contains black iron oxide.

VERAPAMIL (Verapamil Hydrochloride) Injection, USP Ansyr™ Plastic SyringeAmpul Fliptop Vial DESCRIPTION Verapamil hydrochloride is a calcium antagonist or slow-channel inhibitor. Verapamil Hydrochloride Injection, USP is a sterile, nonpyrogenic solution containing verapamil hydrochloride 2.5 mg/mL and sodium chloride 8.5 mg/mL in water for injection. The solution contains no bacteriostat or antimicrobial agent and is intended for single-dose intravenous administration. May contain hydrochloric acid for pH adjustment; pH is 4.9 (4.0 to 6.5). The chemical name of Verapamil Hydrochloride, USP is benzeneacetonitrile, α-[3-[{2-(3,4-dimethoxyphenyl)ethyl} methylamino] propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride. Verapamil hydrochloride is a white or practically white crystalline powder. It is practically odorless and has a bitter taste. It is soluble in water; freely soluble in chloroform; sparingly soluble in alcohol; practically insoluble in ether. It has the following structural formula: Molecular weight: 491.07 Molecular formula: C27H38N2O4• HCl Verapamil hydrochloride is not chemically related to other antiarrhythmic drugs. The plastic syringe is molded from a specially formulated polypropylene. Water permeates from inside the container at an extremely slow rate which will have an insignificant effect on solution concentration over the expected shelf life. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the syringe material.

INDICATIONS Verelan® PM (verapamil hydrochloride extended-release capsules) for oral use is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily stokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Control of high blood pressure should 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. DOSAGE AND ADMINISTRATION THE CONTENTS OF THE Verelan PM CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verelan PM CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE. Essential Hypertension Administer Verelan PM once daily at bedtime. Clinical trials studied doses of 100 mg, 200 mg, 300 mg and 400 mg. The usual daily dose of extended-release Verelan PM in clinical trials has been 200 mg given by mouth once daily at bedtime. In rare instances, initial doses of 100 mg a day may be warranted in patients who have an increased response to verapamil [e.g. patients with impaired renal function, impaired hepatic function, elderly, low-weight patients, etc. (see Use in Specific Populations)]. Base upward titration on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verelan PM are evident within the first week of therapy. If an adequate response is not obtained with 200 mg of Verelan PM, the dose may be titrated upward in the following manner: 300 mg each evening 400 mg each evening (2 × 200 mg) When Verelan PM is administered at bedtime, office evaluation of blood pressure during morning and early afternoon hours is essentially a measure of peak effect. The usual evaluation of trough effect, which sometimes might be needed to evaluate the appropriateness of any given dose of Verelan PM, would be just prior to bedtime. Sprinkling The Capsule Contents On Food Verelan PM capsules may also be administered by carefully opening the capsule and sprinkling the pellets onto one tablespoonful of applesauce. Swallow the applesauce immediately without chewing and follow 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. Use any pellet/applesauce mixture immediately and do not store for future use. Absorption of the pellets sprinkled onto other foods has not been tested. This method of administration may be beneficial for patients who have difficulty swallowing whole capsules. Subdividing the contents of a Verelan PM capsule is not recommended. HOW SUPPLIED Dosage Forms And Strengths Extended-release capsules controlled onset: 100 mg, 200 mg, 300 mg. 100 mg: white opaque cap imprinted SCHWARZ/4085 and amethyst body imprinted 100 mg. 200 mg: amethyst opaque cap imprinted SCHWARZ/4086 and amethyst body imprinted 200 mg. 300 mg: lavender opaque cap imprinted SCHWARZ/4087 and amethyst body imprinted 300 mg. Storage And Handling Verelan PM (verapamil hydrochloride) extended-release pellet filled capsules are supplied in three dosage strengths: 100 mg: Two piece size 2 hard gelatin capsule, white opaque cap imprinted SCHWARZ/4085 and amethyst body imprinted with 100 mg. Product identification printed in black ink, supplied as follows: NDC 0091-4085-01 Bottle of 100s 200 mg: Two piece size 0 hard gelatin capsule, amethyst opaque cap imprinted SCHWARZ/4086 and amethyst body imprinted with 200 mg. Product identification printed in black ink, supplied as follows: NDC 0091-4086-01 Bottle of 100s 300 mg: Two piece size 00 hard gelatin capsule, lavender opaque cap imprinted SCHWARZ/4087 and amethyst body imprinted 300 mg. Product identification printed in black ink, supplied as follows: NDC 0091-4087-01 Bottle of 100s Store at 25°C (77°F); excursions permitted to 15-30°C (59-86°F). [See USP Controlled Room Temperature]. Protect from moisture. Dispense in tight, light-resistant container as defined in USP. Distributed by: Kremers Urban Pharmaceuticals Inc., Princeton, NJ 08540, USA. Manufactured by: Alkermes Gainesville LLC Gainesville, GA 30504, USA. Printed in USA Material Code: Rev. 10/2014

INDICATIONS Verelan (verapamil HCl) is indicated for the treatment of hypertension, to lower blood pressure. Lowering blood pressure reduces the risk of fatal and nonfatal cardiovascular events, primarily strokes and myocardial infarctions. These benefits have been seen in controlled trials of antihypertensive drugs from a wide variety of pharmacologic classes including this drug. Control of high blood pressure should 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. DOSAGE AND ADMINISTRATION Essential Hypertension The dose of Verelan should be individualized by titration. The usual daily dose of sustained-release verapamil, Verelan, in clinical trials has been 240 mg given by mouth once daily in the morning. However, initial doses of 120 mg a day may be warranted in patients who may have an increased response to verapamil (e.g., elderly, small people, etc.). Upward titration should be based on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verelan are evident within the first week of therapy. If adequate response is not obtained with 120 mg of Verelan, the dose may be titrated upward in the following manner: 180 mg in the morning. 240 mg in the morning. 360 mg in the morning. 480 mg in the morning. Verelan sustained-release capsules are for once-a-day administration. When switching from immediaterelease verapamil to Verelan capsules, the same total daily dose of Verelan capsules can be used. As with immediate-release verapamil, dosages of Verelan capsules should be individualized and titration may be needed in some patients. Sprinkling The Capsule Contents On Food Verelan pellet filled 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 Verelan capsule is not recommended. HOW SUPPLIED Verelan® (verapamil hydrochloride) sustained-release pellet filled capsules are supplied in four dosage strengths: 120 mg - Two-piece, size 2 hard gelatin capsule (yellow cap/yellow body), printed with 60274 and 120 mg in black ink, supplied as follows: NDC 62175-580-37 - Bottle of 100s 180 mg - Two-piece, size 1 elongated hard gelatin capsule (light grey cap/yellow body), printed with 60274 and 180 mg in black ink, supplied as follows: NDC 62175-581-37 - Bottle of 100s 240 mg - Two-piece, size 0 hard gelatin capsule (dark blue cap/yellow body), printed with 60274 and 240 mg in black ink, supplied as follows: NDC 62175-582-37 - Bottle of 100s 360 mg - Two-piece, size 00 hard gelatin capsule (lavender cap/yellow body), printed with 60274 and 360 mg in black ink, supplied as follows: NDC 62175-583-37 - Bottle of 100s Store at controlled room temperature 20°-25°C (68°-77°F). [See USP]. Avoid excessive heat. Brief digressions above 25°C, while not detrimental, should be avoided. Protect from moisture. Dispense in tight, light-resistant container as defined in USP. Call your doctor for medical advice about side effects. You may report side effects to Lannett Company, Inc. at 1-844-834-0530 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. Manufactured by: Recro Gainesville LLC Gainesville, GA 30504, USA. Revised: June 2016

INDICATIONS Verapamil Hydrochloride Injection, USP is indicated for the following: Rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardias, including those associated with accessory bypass tracts (Wolff-Parkinson-White [W-P-W] and Lown-Ganong- Levine [L-G-L] syndromes). When clinically advisable, appropriate vagal maneuvers (e.g., Valsalva maneuver) should be attempted prior to verapamil hydrochloride administration. Temporary control of rapid ventricular rate in atrial flutter or atrial fibrillation except when the atrial flutter and/or atrial fibrillation are associated with accessory bypass tracts (Wolff-Parkinson-White (WP- W) and Lown-Ganong-Levine (L-G-L) syndromes). In controlled studies in the United States, about 60% of patients with supraventricular tachycardia converted to normal sinus rhythm within 10 minutes after intravenous verapamil hydrochloride. Uncontrolled studies reported in the world literature describe a conversion rate of about 80%. About 70% of patients with atrial flutter and/or fibrillation with a faster ventricular rate respond with a decrease in ventricular rate of at least 20%. Conversion of atrial flutter or fibrillation to sinus rhythm is uncommon (about 10%) after verapamil hydrochloride and may reflect the spontaneous conversion rate, since the conversion rate after placebo was similar. Slowing of the ventricular rate in patients with atrial fibrillation/flutter lasts 30 to 60 minutes after a single injection. Because as mall fraction ( < 1%) of patients treated with verapamil hydrochloride respond with life-threatening adverseres ponses (rapid ventricular rate in atrial flutter/fibrillation, and an accessory bypass tract, marked hypotension, or extreme bradycardia/asystole – see CONTRAINDICATIONS and WARNINGS), the initial use of verapamil hydrochloride injection should, if possible, be in a treatment setting with monitoring and resuscitation facilities , including D.C.-cardioversion capability (see ADVERSE REACTIONS, Suggested Treatment of Acute Cardiovascular Adverse Reactions ). As familiarity with the patient's response is gained, use in an office setting may be acceptable. Cardioversion has been used safely and effectively after verapamil hydrochloride injection. DOSAGE AND ADMINISTRATION FOR INTRAVENOUS USE ONLY. VERAPAMIL HYDROCHLORIDE INJECTION SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME UNDER CONTINUOUS ELECTROCARDIOGRAPHIC (ECG) AND BLOOD PRESSURE MONITORING. The recommended intravenous doses of verapamil hydrochloride injection are as follows: Adult Initial dose - 5 to 10 mg (0.075 to 0.15 mg/kg body weight) given as an intravenous bolus over at least 2 minutes. Repeat dose - 10 mg (0.15 mg/kg body weight) 30 minutes after the first dose if the initial response is not adequate. An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. Older patients - The dose should be administered over at least 3 minutes to minimize the risk of untoward drug effects. Pediatric Initial dose: 0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range: 0.75 to 2 mg) should be administered as an intravenous bolus over at least 2 minutes under continuous ECG monitoring. 1 to 15 years : 0.1 to 0.3 mg/kg body weight (usual single dose range: 2 to 5 mg) should be administered as an intravenous bolus over at least 2 minutes. Do not exceed 5 mg. Repeat dose 0 to 1 year: 0.1 to 0.2 mg/kg body weight (usual single dose range: 0.75 to 2 mg) 30 minutes after the first dose if the initial response is not adequate (under continuous ECG monitoring). An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. 1 to 15 years : 0.1 to 0.3 mg/kg body weight (usual single dose range: 2 to 5 mg) 30 minutes after the first dose if the initial response is not adequate. Do not exceed 10 mg as a s ingle dos e. An optimal interval for subsequent I.V. doses has not been determined, and should be individualized for each patient. Note: Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. Use only if solution is clear and vial seal is intact. Unused amount of solution should be discarded immediately following withdrawal of any portion of contents. For stability reasons this product is not recommended for dilution with Sodium Lactate Injection, USP inpolyvinyl chloride bags. Verapamil is physically compatible and chemically stable for at least 24 hours at 25°C protected from light in most common large volume parenteral solutions. Admixing verapamil hydrochloride injection with albumin, amphotericin B, hydralazine hydrochloride and trimethoprim with sulfamethoxazole should be avoided. Verapamil hydrochloride injection will precipitate in any solution with a pH above 6.0. HOW SUPPLIED Verapamil Hydrochloride Injection, USP 2.5 mg/mL is supplied in single-dose containers as follows: NDC No. Container Volume Total Content 0409-4011-01 Ampul 2 mL 5 mg 0409-9633-05 ANSYR™ Plastic Syringe 4 mL 10 mg 0409-1144-01 Fliptop Vial 2 mL (5 pack carton) 5 mg 0409-1144-02 Fliptop Vial 4 mL 10 mg 0409-1144-05 Fliptop Vial 2 mL (25 pack tray) 5 mg Store at 20 to 25°C (68 to 77°F). [See USP Controlled Room Temperature.] Protect from light by retaining in package until ready to use. Revised: March, 2010. Hospira, Inc., Lake Forest, IL 60045 USA. Revised: June 2014

PATIENT INFORMATION When the sprinkle method of administration is prescribed, details of the proper technique should be explained to the patient. (See DOSAGE AND ADMINISTRATION.)

PATIENT INFORMATION No information provided. Please refer to the WARNINGS and PRECAUTIONS sections.

OVERDOSE Treatment of overdosage should be supportive and individualized. Beta-adrenergic stimulation and/or parenteral administration of calcium injections may increase calcium ion flux across the slow channel, and have been effectively used in treatment of deliberate overdosage with oral verapamil hydrochloride. Verapamil cannot be removed by hemodialysis. Clinically significant hypotensive reactions or high-degree AV block should be treated with vasopressor agents or cardiac pacing, respectively. Asystole should be handled by the usual measures including isoproterenol hydrochloride, other vasopressor agents, or cardiopulmonary resuscitation (see ADVERSE REACTIONS: Suggested Treatment of Acute Cardiovascular Adverse Reactions ). CONTRAINDICATIONS Verapamil hydrochloride injection is contraindicated in: Severe hypotension or cardiogenic shock. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker). Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil therapy). Patients receiving intravenous beta-adrenergic blocking drugs (e.g., propranolol). Intravenous verapamil and intravenous beta-adrenergic blocking drugs should not be administered in close proximity to each other (within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson- White, Lown-Ganong-Levine syndromes) are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil is administered. Therefore, the use of verapamil in these patients is contraindicated. Ventricular tachycardia: Administration of intravenous verapamil to patients with wide-complex ventricular tachycardia (QRS ≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pretherapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting. Known hypersensitivity to verapamil hydrochloride.

SIDE EFFECTS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates. Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS AND PRECAUTIONS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. The following reactions (Table 1) to orally administered Verelan PM occurred at rates of 2.0% or greater or occurred at lower rates but appeared to be drug-related in clinical trials in hypertension. Table 1: Adverse Events Occurring in 2% of Verelan PM Patients in Placebo-Controlled Clinical Trials All Doses Studied N = 297 % Placebo N = 116 % All Doses Studied N = 297 % Placebo N = 116% Headache 12.1 11.2 Dyspepsia 2.7 1.7 Infection 12.1* 6.9 Rhinitis 2.7 2.6 Constipation 8.8* 0.9 Diarrhea 2.4 1.7 Flu Syndrome 3.7 2.6 Pain 2.4 1.7 Peripheral edema 3.7 0.9 Edema 1.7 0.0 Dizziness 3.0 0.9 Nausea 1.7 0.0 Pharyngitis 3.0 2.6 Accidental Injury 1.5 0.0 Sinusitis 3.0 2.6 *Infection, primarily upper respiratory infection (URI) and unrelated to study medication. Constipation was typically mild and easily manageable. At the usual once-daily dose of 200 mg, the observed incidence of constipation was 3.9%. In previous experience with other formulations of verapamil (N=4,954) the following reactions (Table 2) have occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug related in clinical trials in 4,954 patients. Table 2: Adverse Events Occurring in > 1% (or lower rates and clearly drug related) of Patients with Other Verapamil Formulations Constipation 7.3% Fatigue 1.7% Dizziness 3.3% Bradycardia (HR < 50/min) 1.4% Nausea 2.7% Rash 1.2% Hypotension 2.5% AV block (total 1°, 2°, 3°) 1.2% Headache 2.2% AV block (2° and 3°) 0.8% Edema 1.9% Flushing 0.6% CHF/Pulmonary Edema 1.8% In clinical trials related to the control of ventricular response in patients taking digoxin 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. Open Trials / Postmarketing Experience The following reactions, reported with orally administered verapamil in 2.0% or less of patients, occurred under conditions (open verapamil trials, postmarketing experience [reactions added since the initial US approval of Verelan PM in 1998 are marked with an asterisk]) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: angina pectoris, atrioventricular dissociation, ECG Abnormal*, chest pain, claudication, hypertension*, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive System: diarrhea, dry mouth, elevated liver enzymes* [see WARNINGS AND PRECAUTIONS], 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, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special Senses: blurred vision, tinnitus. Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, impotence, increased urination, spotty menstruation. Other: allergy aggravated, asthenia*. 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, apply the appropriate emergency measures 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, use alphaadrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) to maintain blood pressure, and isoproterenol and avoid norepinephrine. If further support is necessary, inotropic agents (dopamine HCl or dobutamine HCl) may be administered. Actual treatment and dosage depends on the severity of the clinical situation and the judgment and experience of the treating physician. DRUG INTERACTIONS CYP3A4 Inhibitors and Inducers In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics. Inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil. HMG-CoA Reductase Inhibitors The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. Co-administration 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. Grapefruit Juice Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC0-12 ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the pharmacokinetics of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences. 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 extended-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 and propranolol clearance has been observed when either drug is administered concomitantly with verapamil. A variable effect has been seen when verapamil and atenolol were given together. 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 extra-renal clearance of digitoxin 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. Alcohol Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. 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. Telithromycin Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics. Antineoplastic Agents Verapamil can increase doxorubicin levels. The absorption of verapamil can be reduced by the cyclophosphamide, oncovin, procarbazine, prednisone (COPP) and the vindesine, adriamycin, cisplatin (VAC) cytotoxic drug regimens. Concomitant administration of R verapamil can decrease the clearance of paclitaxel. Quinidine In a small number of patients with hypertrophic cardiomyopathy, concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, avoid combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy. 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. Aspirin In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone. 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. Monitor patients receiving these combinations appropriately. 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. Disopyramide Until data on possible interactions between verapamil and disopyramide are obtained, do not administer disopyramide 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. Carbamazepine Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Cyclosporine Verapamil therapy may increase serum levels of cyclosporine. Lithium Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully. Inhalation Anesthetics Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, titrate slowly to avoid excessive cardiovascular depression. Neuromuscular Blocking Agents Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Phenobarbital Phenobarbital therapy may increase verapamil clearance. Rifampin Therapy with rifampin may markedly reduce oral verapamil bioavailability. Theophylline Verapamil may inhibit the clearance and increase the plasma levels of theophylline. Cimetidine The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. 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.

SIDE EFFECTS Serious adverse reactions are uncommon when verapamil HCl therapy is initiated with upward dose titration within the recommended single and total daily dose. See WARNINGS for discussion of heart failure, hypotension, elevated liver enzymes, AV block, and rapid ventricular response. Reversible (upon discontinuation of verapamil) non-obstructive, paralytic ileus has been infrequently reported in association with the use of verapamil. In clinical trials involving 285 hypertensive patients on Verelan for greater than 1 week the following adverse reactions were reported in greater than 1.0% of the patients: Constipation 7.4% Headache 5.3% Dizziness 4.2% Lethargy 3.2% Dyspepsia 2.5% Rash 1.4% Ankle Edema 1.4% Sleep Disturbance 1.4% Myalgia 1.1% In clinical trials of other formulations of verapamil HCl (N=4,954) the following reactions have occurred at rates greater than 1.0%: Constipation 7.3% CHF/Pulmonary Edema 1.8% Dizziness 3.3% Fatigue 1.7% Nausea 2.7% Bradycardia (HR<50/min) 1.4% Hypotension 2.5% AV block-total 1°, 2°, 3° 1.2% 2° and 3° 0.8% Edema 1.9% Headache 2.2% Flushing 0.6% Rash 1.2% 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. DRUG INTERACTIONS Effects Of Other Drugs On Verapamil Pharmacokinetics In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450, -CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, and antibiotic in the ketolide class of antibiotics. HMG-CoA Reductase Inhibitors The use of HMG-CoA reductase inhibitors that are CYP3A4 substrates in combination with verapamil has been associated with reports of myopathy/rhabdomyolysis. Co-administration 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 sustainedrelease 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, angiotensinconverting 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.) Other Aspirin In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone. Cimetidine The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged. Grapefruit juice Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R- verapamil AUC0-12 by 36% and 28%, respectively. Steady state Cmax and Cmin of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, Cmax and Cmin of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the PK of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences. Lithium Pharmacokinetic and pharmacodynamic interactions between oral verapamil and lithium have been reported. The former may result in a lowering of serum lithium levels in patients receiving chronic stable oral lithium therapy. The latter may result in an increased sensitivity to the effects of lithium. Patients receiving both drugs must be monitored carefully. Carbamazepine Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital Phenobarbital therapy may increase verapamil clearance. Cyclosporine Verapamil therapy may increase serum levels of cyclosporine. Inhalation Anesthetics Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression. Neuromuscular Blocking Agents Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

SIDE EFFECTS The following reactions were reported with verapamil hydrochloride injection used in controlled U.S. clinical trials involving 324 patients: Cardiovascular: Symptomatic hypotension (1.5%); bradycardia (1.2%); severe tachycardia (1.0%). The worldwide experience in open clinical trials in more than 7,900 patients was similar. Central Nervous System Effects : Dizziness (1.2%); headache (1.2%). Occasional cases of seizures during verapamil injection have been reported. Gastrointestinal: Nausea (0.9%); abdominal discomfort (0.6%). In rare cases of hypersensitive patients, broncho/laryngeal spasm accompanied by itch and urticaria has been reported. The following reactions have been reported at low frequency: emotional depression, rotary nystagmus, sleepiness, vertigo, muscle fatigue, diaphoresis, and respiratory failure. Suggested Treatment of Acute Cardiovascular Adverse Reactions * The frequency of these adverse reactions was quite low, and experience with their treatment has been limited. Adverse Reaction Proven Effective Treatment Supportive Treatment 1. Symptomatic hypotension requiring treatment Dopamine I.V. Calcium chloride I.V. Norepinephrine bitartrate I.V. Metaraminol bitartrate I.V. Isoproterenol HCl I.V. Intravenous fluids Trendelenburg position 2. Bradycardia, AV block, Asystole Isoproterenol HCl I.V. Calcium chloride I.V. Norepinephrine bitartrate I.V. Atropine I.V. Cardiac pacing Intravenous fluids (slow drip) 3. Rapid ventricular rate (due to antegrade conduction in flutter/fibrillation with W-P-W or L-G-L syndromes) DC-cardioversion (high energy may be required) Procainamide I.V. Lidocaine I.V. Intravenous fluids (slow drip) *Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. DRUG INTERACTIONS (See WARNINGS: Concomitant Antiarrhythmic Therapy.) Verapamil hydrochloride injection has been used concomitantly with other cardioactive drugs (especially digitalis) without evidence of serious negative drug interactions. In rare instances, including when patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction were given intravenous betaadrenergic blocking agents or disopyramide concomitantly with intravenous verapamil, serious adverse effects have occurred. Concomitant use of verapamil hydrochloride with β-adrenergic blockers may result in an exaggerated hypotensive response. Such an effect was observed in one study, following the concomitant administration of verapamil and prazosin. It may be necessary to decrease the dose of verapamil and/or dose of the neuromuscular blocking agent when the drugs are used concomitantly. As verapamil is highly bound to plasma proteins, it should be administered with caution to patients receiving other highly protein-bound drugs. Other Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. In acute studies of healthy volunteers, clearance of verapamil was either reduced or unchanged. Lithium: Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. The addition of verapamil, however, has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully. Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital: Phenobarbital therapy may increase verapamil clearance. Cyclosporin: Verapamil therapy may increase serum levels of cyclosporin. Inhalation Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists (such as verapamil) should be titrated carefully to avoid excessive cardiovascular depression. Neuromuscular Blocking Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of depolarizing and nondepolarizing neuromuscular blocking agents. It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Dantrolene: Two animal studies suggest concomitant intravenous use of verapamil and dantrolene sodium may result in cardiovascular collapse. There has been one report of hyperkalemia and myocardial depression following the coadministration of oral verapamil and intravenous dantrolene.

WARNINGS Included as part of the PRECAUTIONS section. PRECAUTIONS Heart Failure Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In previous clinical experience with 4,954 patients primarily with immediate-release verapamil, 87 (1.8%) developed congestive heart failure or pulmonary edema. Avoid verapamil in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker [see DRUG INTERACTIONS]. Control patients with milder ventricular dysfunction, if possible, with optimum doses of digitalis and/or diuretics before verapamil treatment is started [see DRUG INTERACTIONS]. Hypotension Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels which may result in dizziness or symptomatic hypotension. In hypertensive patients, decreases in blood pressure below normal are unusual. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials of other verapamil formulations was 2.5% [see ADVERSE REACTIONS]. In clinical studies of Verelan PM, 1.7% of the patients developed significant hypotension. 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 in previous verapamil clinical trials [see ADVERSE REACTIONS]. 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 and institution of appropriate therapy depending upon the clinical situation. Patients With Hypertrophic Cardiomyopathy In 120 patients with hypertrophic cardiomyopathy, idiopathic hypertrophic subaortic stenosis (IHSS) (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 history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) pulmonary 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% [see ADVERSE REACTIONS]. 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. Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of Fertility An 18-month toxicity study in rats, at a low multiple (6-fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35 and 120 mg/kg/day or approximately 1.3, 4.4 and 15 times, respectively, the maximum recommended human daily dose (400 mg/day or 8 mg/kg/day). Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation. Studies in female rats at daily dietary doses up to 6.9 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined. Use In Specific Populations Pregnancy Pregnancy Category C Reproduction studies have been performed in rabbits and rats at oral doses up to 1.9 (15 mg/kg/day) and 7.5 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Verapamil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Labor And Delivery It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing Mothers Verapamil is excreted into human milk. In case studies where verapamil concentration in human milk was calculated, the nursing infant doses ranged from less than 0.01% to 0.1% of the mother's verapamil dose. Consider possible infant exposure when verapamil is administered to a nursing woman. Pediatric Use Safety and effectiveness in pediatric patients have not been established. Geriatric Use Clinical studies of Verelan PM were not adequate to determine if subjects aged 65 or over respond differently from younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients; however, greater sensitivity to Verelan PM by some older individuals cannot be ruled out. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly [see CLINICAL PHARMACOLOGY]. Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered [see Use In Specific Populations]. In general, lower initial doses of Verelan PM may be warranted in the elderly [see DOSAGE AND ADMINISTRATION]. Impaired Hepatic Function Since verapamil is highly metabolized by the liver, consider lower dosages and closely monitor responses to the drug in patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Monitor for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects [see OVERDOSAGE] . Impaired Renal Function About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, monitor these patients for abnormal prolongation of the PR interval or other signs of overdosage [see OVERDOSAGE]. Attenuated (decreased) Neuromuscular Transmission It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.

WARNINGS Heart Failure Verapamil has a negative inotropic effect which, in most patients, is compensated by its afterload reduction (decreased systemic vascular resistance) properties without a net impairment of ventricular performance. In clinical experience with 4,954 patients, 87 (1.8%) developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (e.g., ejection fraction less than 30% or moderate to severe symptoms of cardiac failure) and in patients with any degree of ventricular dysfunction if they are receiving a beta-adrenergic blocker. (See DRUG INTERACTIONS.) Patients with milder ventricular dysfunction should, if possible, be controlled with optimum doses of digitalis and/or diuretics before verapamil treatment (note interactions with digoxin under: PRECAUTIONS). Hypotension Occasionally, the pharmacologic action of verapamil may produce a decrease in blood pressure below normal levels 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 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-Parkins On-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. PRECAUTIONS THE CONTENTS OF THE Verelan® CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verelan® CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE (See DOSAGE AND ADMINISTRATION). General Use In Patients With Impaired Hepatic Function Since verapamil is highly metabolized by the liver, it should be administered cautiously to patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediaterelease verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSE) should be carried out. Use In Patients With Attenuated (Decreased) Neuromuscular Transmission It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with 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 OVERDOSE.) Carcinogenesis, Mutagenesis, Impairment Of Fertility An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35 and 120 mg/kg per day or approximately 1x, 3.5x and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day). Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation. Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined. Pregnancy Pregnancy Category C Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the maximum recommended human daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Labor And Delivery It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil HCl in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing Mothers Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric Use Safety and efficacy of verapamil in children below the age of 18 years have not been established. Geriatric Use Clinical studies of verapamil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics And Metabolism). Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered (see PRECAUTIONS, General). In general, lower initial doses of Verelan may be warranted in the elderly (see DOSAGE AND ADMINISTRATION).

WARNINGS VERAPAMIL HYDROCHLORIDE SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME (see DOSAGE AND ADMINISTRATION). Hypotension Verapamil hydrochloride injection often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic but may result in dizziness. Systolic pressure less than 90 mm Hg and/or diastolic pressure less than 60 mm Hg was seen in 5% to 10% of patients in controlled U.S. trials in supraventricular tachycardia and in about 10% of the patients with atrial flutter/fibrillation. The incidence of symptomatic hypotension observed in studies conducted in the U.S. was approximately 1.5%. Three of the five symptomatic patients required intravenous pharmacologic treatment (norepinephrine bitartrate, metaraminol bitartrate, or 10% calcium gluconate). All recovered without sequelae. Extreme Bradycardia/Asystole Verapamil hydrochloride affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients. Bradycardia associated with sick sinus syndrome was reported in 0.3% of the patients treated in controlled double-blind trials in the U.S. The total incidence of bradycardia (ventricular rate less than 60 beats/min) was 1.2% in these studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. (See ADVERSE REACTIONS and Suggested Treatment of Acute Cardiovascular Adverse Reactions.) Heart Failure When heart failure is not severe or rate related, it should be controlled with digitalis glycosides and diuretics, as appropriate, before verapamil is used. In patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen. Concomitant Antiarrhythmic Therapy Digitalis: Verapamil hydrochloride injection has been used concomitantly with digitalis preparations without the occurrence of serious adverse effects. However, since both drugs slow AV conduction, patients should be monitored for AV block or excessive bradycardia. Procainamide: Verapamil hydrochloride injection has been administered to a small number of patients receiving oral procainamide without the occurrence of serious adverse effects. Quinidine: Verapamil hydrochloride injection has been administered to a small number of patients receiving oral quinidine without the occurrence of serious adverse effects. However, three patients have been described in whom the combination resulted in an exaggerated hypotensive response presumably from the combined ability of both drugs to antagonize the effects of catecholamines on α-adrenergic receptors. Caution should therefore be used when employing this combination of drugs. Beta-Adrenergic Blocking Drugs: Verapamil hydrochloride injection has been administered to patients receiving oral beta-blockers without the development of serious adverse effects. However, since both drugs may depress myocardial contractility and AV conduction, the possibility of detrimental interactions should be considered. The concomitant administration of intravenous beta-blockers and intravenous verapamil has resulted in serious adverse reactions (see CONTRAINDICATIONS), especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction. Disopyramide: Until data on possible interactions between verapamil and all forms of 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 reducing myocardial contractility, prolonging AV conduction, and prolonging repolarization. Heart Block: Verapamil prolongs AV conduction time. While high-degree AV block has not been observed in controlled clinical trials in the United States, a low percentage (less than 0.5%) has been reported in the world literature. Development of second- or third-degree AV block or unifascicular, bifascicular, or trifascicular bundle branch block requires reduction in subsequent doses or discontinuation of verapamil and institution of appropriate therapy, if needed. (See ADVERSE REACTIONS, Suggested Treatment of Acute Cardiovascular Adverse Reactions.) Hepatic and Renal Failure: Significant hepatic and renal failure should not increase the effects of a single intravenous dose of verapamil hydrochloride but may prolong its duration. Repeated injections of verapamil hydrochloride injection in such patients may lead to accumulation and an excessive pharmacologic effect of the drug. There is no experience to guide use of multiple doses in such patients, and this generally should be avoided. If repeated injections are essential, blood pressure and PR interval should be closely monitored and smaller repeat doses should be utilized. Verapamil cannot be removed by hemodialysis. Premature Ventricular Contractions: During conversion to normal sinus rhythm, or marked reduction in ventricular rate, a few benign complexes of unusual appearance (sometimes resembling premature ventricular contractions) may be seen after treatment with verapamil hydrochloride. Similar complexes are seen during spontaneous conversion of supraventricular tachycardias, after D.C.-cardioversion and other pharmacologic therapy. These complexes appear to have no clinical significance. Duchenne's Muscular Dystrophy: Verapamil hydrochloride injection can precipitate respiratory muscle failure in these patients and should, therefore, be used with caution. Increased Intracranial Pressure: Verapamil hydrochloride injection has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction. Caution should be taken and appropriate monitoring performed. PRECAUTIONS Pregnancy Teratogenic Effects Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral verapamil doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor And Delivery There have been few controlled studies to determine whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil hydrochloride injection in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor. Nursing Mothers Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. Also, verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered. Pediatric Use Controlled studies with verapamil have not been conducted in pediatric patients, but uncontrolled experience with intravenous administration in more than 250 patients, about half under 12 months of age and about 25% newborn, indicates that results of treatment are similar to those in adults. In rare instances, however, severe hemodynamic side effects - some of them fatal - have occurred following the intravenous administration of verapamil to neonates and infants. Caution should therefore be used when administering verapamil to this group of pediatric patients. The most commonly used single doses in patients up to 12 months of age have ranged from 0.1 to 0.2 mg/kg of body weight, while in patients aged 1 to 15 years, the most commonly used single doses ranged from 0.1 to 0.3 mg/kg of body weight. Most of the patients received the lower dose of 0.1 mg/kg once, but in some cases, the dose was repeated once or twice every 10 to 30 minutes.