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Verapamil HCl Extended-Release Capsules & Tablets

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. PHARMACOKINETICS
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

Verapamil hydrochloride is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist). Verapamil is administered as a racemic mixture of the R and S enantiomers. The structural formulae of the verapamil HCl enantiomers are:

Benzeneacetonitrile, (±)-α-[3 [[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride

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 chemically related to other cardioactive drugs.

Verapamil ER capsules:

Verapamil ER capsule 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.

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 ER tablets:

Verapamil ER tablet is available for oral administration as pale yellow, round, film-coated tablets containing 240 mg of verapamil hydrochloride and as lavender, round, film-coated tablets containing 180 mg of verapamil hydrochloride.

Inactive ingredients: black ferric oxide, BHT, cellulose acetate, hydroxyethyl cellulose, hydroxypropyl cellulose, hypromellose, magnesium stearate, polyethylene glycol, polyethylene oxide, polysorbate 80, povidone, sodium chloride, titanium dioxide, and coloring agents: 240 mg—FD&C Blue No. 2 Lake and D&C Yellow No. 10 Lake; 180 mg—FD&C Blue No. 2 Lake and D&C Red No. 30 Lake.

2. INDICATIONS AND USAGE

Verapamil ER is indicated for the management of hypertension and angina.

3. DOSAGE AND ADMINISTRATION

Verapamil ER should be administered once daily at bedtime. Clinical trials explored dose ranges between 180 mg and 540 mg given at bedtime and found effects to persist throughout the dosing interval.

Verapamil ER tablets should be swallowed whole and not chewed, broken, or crushed.

For both hypertension and angina the dose of verapamil ER should be individualized by titration. Initiate therapy with 180 mg of verapamil ER.

If an adequate response is not obtained with 180 mg of verapamil ER, the dose may be titrated upward in the following manner:

a) 240 mg each evening

b) 360 mg each evening (2 x 180 mg)

c) 480 mg each evening (2 x 240 mg)

When verapamil ER 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 verapamil ER, would be just prior to bedtime.

4. CONTRAINDICATIONS

Verapamil ER is contraindicated in:

1. Severe left ventricular dysfunction (see WARNINGS)

2. Hypotension (systolic pressure less than 90 mm Hg) or cardiogenic shock

3. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker)

4. Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker)

5. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (eg, Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS)

6. Patients with known hypersensitivity to verapamil hydrochloride

5. MECHANISM OF ACTION

Verapamil ER is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) that 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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category C

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.

6.2 Labor 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.

6.3 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.

6.4 Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

6.5 Geriatric Use

Clinical studies of verapamil ER did not include sufficient numbers of subjects aged under 65 to determine whether they responded differently from older 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.

7. WARNINGS AND PRECAUTIONS

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 previous clinical experience with 4,954 patients primarily with immediate-release verapamil, 1.8% developed congestive heart failure or pulmonary edema. Verapamil should be avoided in patients with severe left ventricular dysfunction (eg, 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 is started. (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. In previous verapamil clinical trials the incidence observed in 4,954 patients was 2.5%. In clinical studies of verapamil ER, 0.4% of hypertensive patients and 1.0% of angina patients developed significant hypotension. 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 elevation of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

Accessory bypass tract (Wolff-Parkinson-White or Lown-Ganong-Levine)

Some patients with paroxysmal and/or chronic atrial fibrillation or atrial flutter and a coexisting accessory AV pathway have developed increased antegrade conduction across the accessory pathway bypassing the AV node, producing a very rapid ventricular response or ventricular fibrillation after receiving intravenous verapamil (or digitalis). Although a risk of this occurring with oral verapamil has not been established, such patients receiving oral verapamil may be at risk and its use in these patients is contraindicated (see CONTRAINDICATIONS). Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

Atrioventricular block

The effect of verapamil on AV conduction and the SA node may cause asymptomatic first-degree AV block and transient bradycardia, sometimes accompanied by nodal escape rhythms. PR-interval prolongation is correlated with verapamil plasma concentrations, especially during the early titration phase of therapy. Higher degrees of AV block, however, were infrequently (0.8%) observed in previous verapamil clinical trials. 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 (greater than 20 mm Hg) pulmonary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine (see Drug interactions) preceded the severe hypotension in 3 of the 8 patients (2 of whom developed pulmonary edema). Sinus bradycardia occurred in 11% of the patients, second-degree AV block in 4%, and sinus arrest in 2%. It must be appreciated that this group of patients had a serious disease with a high mortality rate. Most adverse effects responded well to dose reduction, and only rarely did verapamil use have to be discontinued.

PRECAUTIONS

General

Formulation specific

As with any other non-deformable dosage form caution should be used when administering verapamil ER in patients with preexisting severe gastrointestinal narrowing (pathologic or iatrogenic). In patients with extremely short GI transit time (<7 hrs), pharmacokinetic data are not available and dosage adjustment may be required.

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 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. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE) 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, 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. Verapamil is not removed by hemodialysis. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage (see OVERDOSAGE).

8. ADVERSE REACTIONS

Serious adverse reactions are uncommon when verapamil 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. The following reactions to orally administered COVERA-HS occurred at rates greater than 2.0% or occurred at lower rates but appeared drug-related in clinical trials in hypertension and angina:

Table 1. Adverse Reactions Occured at ≥ 2% or Drug-Related

* Constipation was typically mild, easily manageable, and the incidence usually diminished within about one week. At a typical once daily dose of 240 mg, the observed incidence was 7.2%.

In previous experience with other formulations of verapamil, the following reactions 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 Reactions of Other Formulations of Verapamil Occured at ≥ 1% or Drug-Related

Treatment of acute cardiovascular adverse reactions

The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited.

Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately; eg, intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol HCl (all in usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alphaadrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, dopamine HCl or dobutamine HCl may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgement and experience of the treating physician.

9. OVERDOSAGE

Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially sustained-release verapamil products), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustainedrelease formulation. Verapamil is known to decrease gastrointestinal transit time.

Treatment of overdosage should be supportive. Beta-adrenergic stimulation or parenteral administration of calcium solutions may increase calcium ion flux across the slow channel and have been used effectively in treatment of deliberate overdosage with verapamil. In a few reported cases, overdose with calcium channel blockers has been associated with hypotension and bradycardia, initially refractory to atropine but becoming more responsive to this treatment when the patients received large doses (close to 1 gram/hour for more than 24 hours) of calcium chloride. 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 cardiopulmonary resuscitation.

10. 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 (eg, erythromycin, ritonavir) causing elevation of plasma levels of verapamil while inducers of CYP3A4 (eg, rifampin) have caused a lowering of plasma levels of verapamil.

Alcohol

Verapamil may increase blood alcohol concentrations and prolong its effects.

Aspirin

In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.

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 PK 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 sustained-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excessive bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risks 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

Clinical use of verapamil in digitalized patients has shown the combination to be well tolerated if digoxin doses are properly adjusted. However, 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 kinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digitoxin by 27% and 29%, respectively. Maintenance and digitalization doses should be reduced when verapamil is administered, and the patient should be reassessed to avoid over- to under-digitalization. Whenever over-digitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of verapamil use, the patient should be reassessed to avoid under-digitalization. In previous clinical trials with other verapamil formulations related to the control of ventricular response in digitalized patients 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 (eg, vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta-blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in a 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 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 electrophysiologic 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.

Other agents

Nitrates

Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and clinical experience suggest beneficial interactions.

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.

Lithium

Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy; lithium levels have been observed sometimes to increase, sometimes to decrease, and sometimes to be unchanged. 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.

Theophylline

Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

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 channel blocking agents, such as verapamil, should each 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.

Telithromycin

Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class.

11. 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. 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. 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 and 50 times the activity of the R enantiomer in reducing myocardial contractility in isolated blood-perfused dog papillary muscle and isolated rabbit 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 at night had no effect on the pharmacokinetics of verapamil ER. The pharmacokinetics were also not affected by whether the volunteers were supine or ambulatory for the 8 hours following dosing. Administering verapamil ER in the morning led to a slower rate of absorption and/or elimination, but did not affect the extent of absorption or extent of metabolism to norverapamil.

Orally administered verapamil undergoes extensive metabolism in the liver. 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. 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 PRECAUTIONS). 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.

Geriatric use

The pharmacokinetics of verapamil ER 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 AUC0-24 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). These results were typical of the age-related differences seen with many drug products in clinical medicine. Lean body mass was inversely related to AUC, but no gender difference was observed in the clinical trials of verapamil ER. However, there are conflicting data in the literature suggesting that verapamil clearance may decrease with age in women to a greater degree than in men. Mean Tmax was similar in young and elderly subjects.

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. Improved left ventricular diastolic function in patients with Idiopathic Hypertrophic Subaortic Stenosis (IHSS) and those with coronary heart disease has also been observed with verapamil. In patients with severe left ventricular dysfunction (eg, pulmonary wedge pressure above 20 mm Hg or ejection fraction less than 30%), or in patients taking beta-adrenergic blocking agents or other cardiodepressant drugs, deterioration of ventricular function may occur (see PRECAUTIONS, Drug interactions).

Pulmonary function

Verapamil 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.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand names: COVERA-HS, by GD SEARLE LLC.

VERELAN, by Elan Pharma.

VERELAN PM, by Elan Pharma.

ISOPTIN SR (discontinued), by FSC.

b) Generic drugs

COVERA-HS equivalent drugs: None.

VERELAN, VERELAN PM equivalent drugs: Verapamil HCl, by Mylan.

2) How Supplied:

Verapamil HCl ER capsules (by Mylan):

Verapamil Hydrochloride extended-release capsules, are available in 120 mg, 180 mg and 240 mg capsules.

The 120 mg capsule is a bluish green opaque cap/white opaque body, hard-shell gelatin capsule filled with white to off-white beads. The capsule is radially printed with MYLAN over 6320 in black ink on both the cap and the body. They are available as follows:

NDC 0378-6320-93 bottles of 30 capsules

NDC 0378-6320-01 bottles of 100 capsules

NDC 0378-6320-05 bottles of 500 capsules

The 180 mg capsule is a bluish green opaque cap/light green opaque body, hard-shell gelatin capsule filled with white to off-white beads. The capsule is radially printed with MYLAN over 6380 in black ink on both the cap and the body. They are available as follows:

NDC 0378-6380-93 bottles of 30 capsules

NDC 0378-6380-01 bottles of 100 capsules

NDC 0378-6380-05 bottles of 500 capsules

The 240 mg capsule is a bluish green opaque cap/bluish green opaque body, hard-shell gelatin capsule filled with white to off-white beads. The capsule is radially printed with MYLAN over 6440 in black ink on both the cap and the body. They are available as follows:

NDC 0378-6440-93 bottles of 30 capsules

NDC 0378-6440-01 bottles of 100 capsules

NDC 0378-6440-05 bottles of 500 capsules

Verapamil HCl tablets:

Covera-HS 180-mg tablets are lavender, round, film coated, with COVERA–HS 2011 printed on one side, supplied as:

NDC Number: 0025-2011-31 bottle of 100

Covera-HS 240-mg tablets are pale yellow, round, film coated with COVERA–HS 2021 printed on one side, supplied as:

NDC Number: 0025-2021-31 bottle of 100

3) Storage: Store at controlled room temperature 20°–25°C (68°–77°F) [see USP]. Dispense in tight, light-resistant containers.

Rx only

Rev 10/11