Verapamil Hydrochloride Tablets, USP 40 mg and 120 mg

DESCRIPTION

id: 40e2f725-1bc4-4652-e054-00144ff88e88
displayName: DESCRIPTION SECTION
FDA Article Code: 34089-3

    Verapamil hydrochloride (verapamil HCl) is a calcium ion influx inhibitor (slow-channel blocker or calcium ion antagonist) available for oral administration in film-coated tablets containing 40 mg, or 120 mg of verapamil hydrochloride. The structural formula of verapamil HCl is:

C
₂₇
H
₃₈
N
₂
O
₄
• HCl M.W. = 491.08 Benzeneacetonitrile, a-[3-[[2-(3,4-dimethoxyphenyl)ethyl] methylamino]propyl]-3,4-dimethoxy-a-(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. Inactive ingredients include colloidal silicon dioxide, dibasic calcium phosphate dihydrate, magnesium stearate, microcrystalline cellulose, sodium starch glycolate, light mineral oil, sodium lauryl sulfate, titanium dioxide and hypromellose.

CLINICAL PHARMACOLOGY

id: 40e2f725-1bc5-4652-e054-00144ff88e88
displayName: CLINICAL PHARMACOLOGY SECTION
FDA Article Code: 34090-1

Verapamil hydrochloride 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.

INDICATIONS AND USAGE

id: 40e2f725-1bc7-4652-e054-00144ff88e88
displayName: INDICATIONS & USAGE SECTION
FDA Article Code: 34067-9

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 1.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 ) 2.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.

CONTRAINDICATIONS

id: 40e2f725-1bc8-4652-e054-00144ff88e88
displayName: CONTRAINDICATIONS SECTION
FDA Article Code: 34070-3

Verapamil HCl 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 (e.g., Wolff-Parkinson-White, Lown-Ganong-Levine syndromes) (see WARNINGS ) 6.Patients with known hypersensitivity to verapamil hydrochloride

WARNINGS

id: 40e2f725-1bc9-4652-e054-00144ff88e88
displayName: WARNINGS SECTION
FDA Article Code: 34071-1

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 PRECAUTIONS, 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 with 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 hydrochloride. 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. 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 on 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 PRECAUTIONS, 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.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY

id: 40e2f725-1bd2-4652-e054-00144ff88e88
displayName: ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION
FDA Article Code: 34091-9

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.

ADVERSE REACTIONS

id: 40e2f725-1bd3-4652-e054-00144ff88e88
displayName: ADVERSE REACTIONS SECTION
FDA Article Code: 34084-4

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), alpha¬;;;adrenergic 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.

OVERDOSAGE

id: 40e2f725-1bd4-4652-e054-00144ff88e88
displayName: OVERDOSAGE SECTION
FDA Article Code: 34088-5

Treat all verapamil overdoses as serious and maintain observation for at least 48 hours (especially Verapamil Hydrochloride Tablets SR), preferably under continuous hospital care. Delayed pharmacodynamic consequences may occur with the sustained-release 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.

DOSAGE AND ADMINISTRATION

id: 40e2f725-1bd5-4652-e054-00144ff88e88
displayName: DOSAGE & ADMINISTRATION SECTION
FDA Article Code: 34068-7

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.

HOW SUPPLIED

id: 415eab97-9092-2d5e-e054-00144ff88e88
displayName: HOW SUPPLIED SECTION
FDA Article Code: 34069-5

Verapamil Hydrochloride Tablets, USP 120 mg tablets are round, standard concave, white film-coated, scored, debossed “HP” above and “27” below on one side and plain on the reverse side, supplied as: NDC Number 66267-294-90 Bottle of 90 Store at 20° to 25°C (68° to 77°F) [See USP controlled room temperature] and protect from light. Dispense in a tight, light-resistant container using a child-resistant closure. MANUFACTURED FOR: Heritage Pharmaceuticals Inc. Eatontown, NJ 07724 1.866.901.DRUG (3784) 51U000000252US04 Issued: 09/16

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

id: 415ed6c4-a3db-37cb-e054-00144ff8d46c
displayName: PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
FDA Article Code: 51945-4