VERAPAMIL HYDROCHLORIDE

INDICATIONS AND USAGE Verapamil hydrochloride tablets, USP are indicated for the treatment of the following: Angina 1. Angina at rest including: Vasospastic (Prinzmetal's variant) angina Unstable (crescendo, pre-infarction) angina 2. Chronic stable angina (classic effort-associated angina) Arrhythmias In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS : Accessory bypass tract) Prophylaxis of repetitive paroxysmal supraventricular tachycardia Essential hypertension Verapamil hydrochloride 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.

Angina 1. Angina at rest including: Vasospastic (Prinzmetal's variant) angina Unstable (crescendo, pre-infarction) angina 2. Chronic stable angina (classic effort-associated angina)

Arrhythmias In association with digitalis for the control of ventricular rate at rest and during stress in patients with chronic atrial flutter and/or atrial fibrillation (see WARNINGS : Accessory bypass tract) Prophylaxis of repetitive paroxysmal supraventricular tachycardia

Essential hypertension Verapamil hydrochloride 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, a …

DOSAGE AND ADMINISTRATION The dose of verapamil must be individualized by titration. The usefulness and safety of dosages exceeding 480 mg/day have not been established; therefore, this daily dosage should not be exceeded. Since the half-life of verapamil increases during chronic dosing, maximum response may be delayed. Angina : Clinical trials show that the usual dose is 80 mg to 120 mg three times a day. However, 40 mg three times a day may be warranted in patients who may have an increased response to verapamil (e.g., decreased hepatic function, elderly, etc). Upward titration should be based on therapeutic efficacy and safety evaluated approximately eight hours after dosing. Dosage may be increased at daily (e.g., patients with unstable angina) or weekly intervals until optimum clinical response is obtained. Arrhythmias : The dosage in digitalized patients with chronic atrial fibrillation ( see PRECAUTIONS ) ranges from 240 to 320 mg/day in divided (t.i.d. or q.i.d.) doses. The dosage for prophylaxis of PSVT (non-digitalized patients) ranges from 240 to 480 mg/day in divided (t.i.d. or q.i.d.) doses. In general, maximum effects for any given dosage will be apparent during the first 48 hours of therapy. Essential hypertension: Dose should be individualized by titration. The usual initial monotherapy dose in clinical trials was 80 mg three times a day (240 mg/ day). Daily dosages of 360 and 480 mg have been used but there is no evidence that dosages beyond 360 mg provided added effect. Consideration should be given to beginning titration at 40 mg three times per day in patients who might respond to lower doses, such as the elderly or people of small stature. The antihypertensive effects of verapamil hydrochloride are evident within the first week of therapy. Upward titration should be based on therapeutic efficacy, assessed at the end of the dosing interval.

CONTRAINDICATIONS Verapamil HCl extended-release tablets are 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

ADVERSE REACTIONS Serious adverse reactions are uncommon when verapamil hydrochloride 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 verapamil occurred at rates greater than 1.0% or occurred at lower rates but appeared clearly drug-related in clinical trials in 4,954 patients: Constipation 7.30% Dyspnea 1.40% Dizziness 3.30% Bradycardia (HR <50/min) 1.40% Nausea 2.70% AV block total (1°, 2°, 3°) 1.20% Hypotension 2.50% 2° and 3° 0.80% Headache 2.20% Rash 1.20% Edema 1.90% Flushing 0.60% CHF, Pulmonary edema 1.80% Fatigue 1.70% Elevated liver enzymes (see WARNINGS ) In clinical trials related to the control of ventricular response in digitalized patients who had atrial fibrillation or flutter, ventricular rates below 50 at rest occurred in 15% of patients and asymptomatic hypotension occurred in 5% of patients. The following reactions, reported in 1.0% or less of patients, occurred under conditions (open trials, marketing experience) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular: angina pectoris, atrioventricular dissociation, chest pain, claudication, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive system : diarrhea, dry mouth, gastrointestinal distress, gingival hyperplasia. Hemic and lymphatic: ecchymosis or bruising. Nervous system: cerebrovascular accident, confusion, equilibrium disorders, insomnia, muscle cramps, paresthesia, psychotic symptoms, shakiness, somnolence, extrapyramidal symptoms. Skin: arthralgia and rash, exanthema, hair loss, hyperkeratosis, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special senses: blurred vision, tinnitus. Urogenital: gynecomastia, galactorrhea/hyperprolactinemia, increased urination, spotty menstruation, impotence. Treatment of acute cardiovascular adverse reactions: The frequency of cardiovascular adverse reactions that require therapy is rare; hence, experience with their treatment is limited. Whenever severe hypotension or complete AV block occurs following oral administration of verapamil, the appropriate emergency measures should be applied immediately; e.g., intravenously administered norepinephrine bitartrate, atropine sulfate, isoproterenol HCl (all in the usual doses), or calcium gluconate (10% solution). In patients with hypertrophic cardiomyopathy (IHSS), alphaadrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) should be used to maintain blood pressure, and isoproterenol and norepinephrine should be avoided. If further support is necessary, dopamine HCl or dobutamine HCl may be administered. Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician. To report SUSPECTED ADVERSE REACTIONS contact AvKARE at 1-855-361-3993; email drugsafety@avkare.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug interactions Cytochrome inducers/inhibitors: In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450 CYP3A4, CYP1A2, CYP2C8, CYP2C9, and CYP2C18. 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. 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. Ivabradine: Concurrent use of verapamil increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid co-administration of verapamil and ivabradine. 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 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 carefully monitored to avoid over- or under-digitalization. Whenever over-digitalization is suspected, the daily dose of digitalis should be reduced or temporarily discontinued. On discontinuation of verapamil hydrochloride use, the patient should be reassessed to avoid under-digitalization. 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 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 phosphate are obtained, disopyramide should not be administered within 48 hours b …

Mechanism of action Essential hypertension: Verapamil exerts antihypertensive effects by decreasing systemic vascular resistance, usually without orthostatic decreases in blood pressure or reflex tachycardia; bradycardia (rate less than 50 beats/min) is uncommon (1.4%). During isometric or dynamic exercise, verapamil hydrochloride does not alter systolic cardiac function in patients with normal ventricular function. Verapamil hydrochloride does not alter total serum calcium levels. However, one report suggested that calcium levels above the normal range may alter the therapeutic effect of verapamil hydrochloride. Other pharmacologic actions of Verapamil Hydrochloride include the following: Verapamil hydrochloride dilates the main coronary arteries and coronary arterioles, both in normal and ischemic regions, and is a potent inhibitor of coronary artery spasm, whether spontaneous or ergonovine-induced. This property increases myocardial oxygen delivery in patients with coronary artery spasm and is responsible for the effectiveness of verapamil hydrochloride in vasospastic (Prinzmetal's or variant) as well as unstable angina at rest. Whether this effect plays any role in classical effort angina is not clear, but studies of exercise tolerance have not shown an increase in the maximum exercise rate–pressure product, a widely accepted measure of oxygen utilization. This suggests that, in general, relief of spasm or dilation of coronary arteries is not an important factor in classical angina. Verapamil hydrochloride 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. Electrical activity through the AV node depends, to a significant degree, upon calcium influx through the slow channel. By decreasing the influx of calcium, verapamil hydrochloride prolongs the effective refractory period within the AV node and slows AV conduction in a rate-related manner. Normal sinus rhythm is usually not affected, but in patients with sick sinus syndrome, verapamil hydrochloride may interfere with sinus-node impulse generation and may induce sinus arrest or sinoatrial block. Atrioventricular block can occur in patients without preexisting conduction defects (see WARNINGS ). Verapamil hydrochloride 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 hydrochloride may shorten the antegrade effective refractory period of the accessory bypass tract. Acceleration of ventricular rate and/or ventricular fibrillation has been reported in patients with atrial flutter or atrial fibrillation and a coexisting accessory AV pathway following administration of verapamil (see WARNINGS ). Verapamil hydrochloride has a local anesthetic action that is 1.6 times that of procaine on an equimolar basis. It is not known whether this action is important at the doses used in man. Pharmacokinetics and metabolism: With the immediate-release formulation, more than 90% of the orally administered dose of verapamil hydrochloride is absorbed. Because of rapid biotransformation of verapamil during its first pass through the portal circulation, bioavailability ranges from 20% to 35%. Peak plasma concentrations are reached between 1 and 2 hours after oral administration. Chronic oral administration of 120 mg of verapamil hydrochloride every 6 hours resulted in plasma levels of verapamil ranging from 125 ng/mL to 400 ng/mL, with higher values reported occasionally. A nonlinear correlation between the verapamil dose administered and verapamil plasma level does exist. In early dose titration with verapamil, a relationship exists between verapamil plasma concentration and prolongation of the PR interval. However, during chronic administration this relationship may disappear. The mean elimination half-life in single-dose studies range …

DESCRIPTION Verapamil hydrochloride extended-release tablets, USP (verapamil hydrochloride) is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist). Verapamil hydrochloride extended-release tablets, USP are available for oral administration as beige colored, biconvex, modified capsule shaped, scored, film-coated tablets containing 240 mg of verapamil hydrochloride (equivalent to 222.16 mg verapamil free base); as beige colored, oval shaped, biconvex, scored, film-coated tablets containing 180 mg of verapamil hydrochloride (equivalent to 166.62 mg verapamil free base); and as light beige colored, oval shaped, biconvex, film-coated tablets containing 120 mg of verapamil hydrochloride (equivalent to 111.08 mg verapamil free base). The tablets are designed for extended-release of the drug in the gastrointestinal tract; extended-release characteristics are not altered when the tablet is divided in half. The structural formula of verapamil HCl, USP is: C 27 H 39 ClN 2 O 4 M.W = 491.06 Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)-ethyl]methylamino]propyl]-3,4-dimethoxy-α-(1-methylethyl) hydrochloride Verapamil HCl, USP is white or practically white crystalline powder. Is practically odourless and has a bitter taste. It is soluble in water, freely soluble in chloroform, sparingly soluble in alcohol and practically insoluble in ether. Verapamil HCl, USP is not chemically related to other cardioactive drugs. Inactive ingredients include hypromellose, isopropyl alcohol, magnesium stearate, macrogol, microcrystalline cellulose 102, povidone, sodium alginate, talc, titanium dioxide and coloring agents: - iron oxide yellow and iron oxide red. FDA approved dissolution test specifications differ from USP. Image

OVERDOSAGE Overdose with verapamil may lead to pronounced hypotension, bradycardia, and conduction system abnormalities (eg, junctional rhythm with AV dissociation and high degree AV block, including asystole). Other symptoms secondary to hypoperfusion (e.g., metabolic acidosis, hyperglycemia, hyperkalemia, renal dysfunction, and convulsions) may be evident. Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially verapamil hydrochloride extended-release), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the extended-release formulation. Verapamil is known to decrease gastrointestinal transit time. In overdose, extended-release tablets of verapamil hydrochloride have occasionally been reported to form concretions within the stomach or intestines. These concretions have not been visible on plain radiographs of the abdomen, and no medical means of gastrointestinal emptying is of proven efficacy in removing them. Endoscopy might reasonably be considered in cases of massive overdose when symptoms are unusually prolonged. 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. Continued treatment with large doses of calcium may produce a response. In a few reported cases, overdose with calcium channel blockers that was initially refractory to atropine became more responsive to this treatment when the patients received large doses (close to 1 g/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.

HOW SUPPLIED Verapamil hydrochloride extended-release tablets, USP, 120 mg are light beige colored, oval shaped, biconvex, film coated tablets, debossed with '61' on one side and '5' on the other side, supplied as: NDC Number 68382-561-01 bottle of 100 with child-resistant closure 68382-561-05 bottle of 500 Verapamil hydrochloride extended-release tablets, USP, 180 mg are beige colored, oval shaped, biconvex, film coated tablets, debossed with '562' on one side and scored on the other side, supplied as: NDC Number 68382-562-01 bottle of 100 with child-resistant closure 68382-562-05 bottle of 500 Verapamil hydrochloride extended-release tablets, USP, 240 mg are beige colored, biconvex, modified capsule shaped, film coated tablets, debossed with '563' on one side and scored on other side, supplied as: NDC Number 68382-563-01 bottle of 100 with child-resistant closure 68382-563-05 bottle of 500 Store at 20o to 25oC (68o to 77oF); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Protect from Light and Moisture. Manufactured by: Zydus Lifesciences Ltd., Baddi-173205, India. Distributed by: Zydus Pharmaceuticals (USA) Inc. Pennington, NJ 08534 Rev. 12/25