VERAPAMIL HYDROCHLORIDE

Verapamil hydrochloride sustained-release capsules are calcium ion influx inhibitors (slow channel blockers or calcium ion antagonists). Verapamil hydrochloride sustained-release capsules are 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: C 27 H 38 N 2 O 4 •HCl M.W. 491.07 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 verapamil hydrochloride sustained-release capsules contain the following inactive ingredients: fumaric acid, talc, sugar spheres, povidone, shellac, gelatin, FD&C red #40, yellow iron oxide, titanium dioxide, silicon dioxide, and sodium lauryl sulfate. In addition, the verapamil hydrochloride sustained-release capsules 240 mg and 360 mg capsules contain FD&C blue #1 and D&C red #28; and the verapamil hydrochloride sustained-release capsules 180 mg contain black iron oxide. verapamil hydrochloride structural formula

Verapamil hydrochloride sustained-release capsules are 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 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.

Essential Hypertension The dose of verapamil hydrochloride sustained-release capsules should be individualized by titration. The usual daily dose of sustained-release verapamil, verapamil hydrochloride sustained-release capsules, 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 verapamil hydrochloride sustained-release capsules are evident within the first week of therapy. If adequate response is not obtained with 120 mg of verapamil hydrochloride sustained-release capsules, the dose may be titrated upward in the following manner: (a) 180 mg in the morning. (b) 240 mg in the morning. (c) 360 mg in the morning. (d) 480 mg in the morning. Verapamil hydrochloride sustained-release capsules are for once-a-day administration. When switching from immediate-release verapamil to verapamil hydrochloride sustained-release capsules, the same total daily dose of verapamil hydrochloride sustained-release capsules can be used. As with immediate-release verapamil, dosages of verapamil hydrochloride sustained-release capsules should be individualized and titration may be needed in some patients. Sprinkling the Capsule Contents on Food Verapamil hydrochloride sustained-release capsules may also be administered by carefully opening the capsule and sprinkling the pellets on a spoonful of applesauce. The applesauce should be swallowed immediately without chewing and followed with a glass of cool water to ensure complete swallowing of the pellets. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Any pellet/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a verapamil hydrochloride sustained-release capsule is not recommended.

Verapamil HCl is contraindicated in: Severe left ventricular dysfunction. (See WARNINGS . ) Hypotension (less than 90 mm Hg systolic pressure) or cardiogenic shock. Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker). Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes). (See WARNINGS . ) Patients with known hypersensitivity to verapamil hydrochloride.

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 verapamil hydrochloride sustained-release capsules 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% Dizziness 3.3% Nausea 2.7% Hypotension 2.5% Edema 1.9% Headache 2.2% Rash 1.2% CHF/Pulmonary Edema 1.8% Fatigue 1.7% Bradycardia (HR<50/min) 1.4% AV block-total 1°, 2°, 3° 1.2% 2° and 3° 0.8% Flushing 0.6% Elevated Liver Enzymes (See WARNINGS ) In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or atrial flutter, ventricular rate below 50/min at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive System: diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. Hemic and Lymphatic: ecchymosis or bruising. Nervous System: cerebrovascular accident, confusion, equilibrium disorders, extrapyramidal symptoms, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence. Respiratory: dyspnea. Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, maculae, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special Senses: blurred vision, tinnitus. Urogenital: gynecomastia, impotence, increased urination, spotty menstruation. Treatment of Acute Cardiovascular Adverse Reactions The frequency of cardiovascular adverse reactions which require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately, e.g., intravenously administered isoproterenol HCl, levarterenol bitartrate, atropine (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alpha-adrenergic agents (phenylephrine, metaraminol bitartrate or methoxamine) should be used to maintain blood pressure, and isoproterenol and levarterenol should be avoided. If further support is necessary, inotropic agents (dopamine or dobutamine) may be administered. Actual treatment and dosage should depend on the severity and the clinical situation and the judgment and experience of the treating physician. To report SUSPECTED ADVERSE EVENTS, contact Wilshire Pharmaceuticals, Inc. at 1-877-495-6856 or FDA at 1-800-FDA-1088 or http://www.fda.gov/medwatch for voluntary reporting of adverse reactions.

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, an antibiotic in the ketolide class of antibiotics. Ivabradine Concurrent use of verapamil increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and 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. Beta Blockers Concomitant therapy with beta-adrenergic blockers and verapamil may result in additive negative effects on heart rate, atrioventricular conduction, and/or cardiac contractility. The combination of sustained-release verapamil and beta-adrenergic blocking agents has not been studied. However, there have been reports of excess bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risk of combined therapy may outweigh the potential benefits. The combination should be used only with caution and close monitoring. Asymptomatic bradycardia (36 beats/min) with a wandering atrial pacemaker has been observed in a patient receiving concomitant timolol (a beta-adrenergic blocker) eyedrops and oral verapamil. A decrease in metoprolol clearance has been reported when verapamil and metoprolol were administered together. A similar effect has not been observed when verapamil and atenolol are given together. Clonidine Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine. Digitalis Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor digoxin level periodically during therapy. Chronic verapamil treatment can increase serum digoxin levels by 50% to 75% during the first week of therapy, and this can result in digitalis toxicity. In patients with hepatic cirrhosis the influence of verapamil on digoxin pharmacokinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digoxin by 27% and 29%, respectively. If digoxin toxicity is suspected, suspend or discontinue digoxin therapy. In previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients. Antihypertensive Agents Verapamil administered concomitantly with oral antihypertensive agents (e.g., vasodilators, angiotensin-converting enzyme inhibitors, diuretics, beta blockers) will usually have an additive effect on lowering blood pressure. Patients receiving these combinations should be appropriately monitored. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in reduction in blood pressure that is excessive in some patients. Such an effect was observed in one study following the concomitant administration of verapamil and prazosin. Antiarrhythmic Agents Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction. Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy. Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. Alcohol: Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism .)

Store at Controlled Room Temperature 20° to 25°C (68° to 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.