Professional Information — Verapamil Hydrochloride

Indications and Usage

Verapamil hydrochloride extended-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’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 verapamil hydrochloride extended-release capsules should be individualized by titration. The usual daily dose of extended-release, verapamil hydrochloride 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 extended-release capsules are evident within the first week of therapy.

If adequate response is not obtained with 120 mg of verapamil hydrochloride extended-release capsules, the dose may be titrated upward in the following manner:

1. (a)180 mg in the morning.
2. (b)240 mg in the morning.
3. (c)360 mg in the morning.
4. (d)480 mg in the morning.

Verapamil extended-release capsules are for once-a-day administration. When switching from immediate-release verapamil to verapamil hydrochloride extended-release capsules, the same total daily dose of verapamil hydrochloride extended-release capsules can be used.

As with immediate-release verapamil, dosages of verapamil hydrochloride extended-release capsules should be individualized and titration may be needed in some patients.

Sprinkling the Capsule Contents on Food

Verapamil hydrochloride extended-release bead filled capsules may also be administered by carefully opening the capsule and sprinkling the beads 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 beads. The applesauce used should not be hot, and it should be soft enough to be swallowed without chewing. Any bead/applesauce mixture should be used immediately and not stored for future use. Subdividing the contents of a verapamil hydrochloride extended-release capsule is not recommended.

Contraindications

Verapamil HCl is contraindicated in:

1. 1.Severe left ventricular dysfunction. (See WARNINGS.)
2. 2.Hypotension (less than 90 mmHg systolic pressure) or cardiogenic shock.
3. 3.Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker).
4. 4.Second- or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker).
5. 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. 6.Patients with known hypersensitivity to verapamil hydrochloride.

Adverse Reactions

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 extended-release capsules for greater than 1 week the following adverse reactions were reported in greater than 1.0% of the patients:

In clinical trials of other formulations of verapamil HCl (N = 4,954) the following reactions have occurred at rates greater than 1.0%:

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.

Overdosage

There is no specific antidote for verapamil overdosage; treatment should be supportive. Delayed pharmacodynamic consequences may occur with extended-release formulations, and patients should be observed for at least 48 hours, preferably under continuous hospital care. Reported effects include hypotension, bradycardia, cardiac conduction defects, arrhythmias, hyperglycemia, and decreased mental status. In addition, there have been literature reports of non-cardiogenic pulmonary edema in patients taking large overdoses of verapamil (up to approximately 9 g).

In acute overdosage, gastrointestinal decontamination with cathartics and whole bowel irrigation should be considered. Calcium, inotropes (i.e., isoproterenol, dopamine, and glucagon), atropine, vasopressors (i.e., norepinephrine, and epinephrine), and cardiac pacing have been used with variable results to reverse hypotension and myocardial depression. 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. Calcium chloride is preferred to calcium gluconate since it provides 3 times more calcium per volume. Asystole should be handled by the usual measures including cardiopulmonary resuscitation. Verapamil cannot be removed by hemodialysis.

Description

Verapamil hydrochloride extended-release capsules, USP are a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist). Verapamil hydrochloride extended-release capsules are available for oral administration as a 120 mg hard gelatin capsule (bluish green opaque cap and white opaque body), a 180 mg hard gelatin capsule (bluish green opaque cap and light green opaque body) and a 240 mg hard gelatin capsule (bluish green opaque cap and bluish green opaque body). These bead filled capsules provide an extended-release of the drug in the gastrointestinal tract.

The structural formula of verapamil HCl is given below:

Chemical name: (±)-5-[(3,4-Dimethoxyphenethyl)methylamino]-2-(3,4-dimethoxyphenyl)-2-isopropylvaleronitrile monohydrochloride.

Verapamil HCl, USP is a white or 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 extended-release capsules contain the following inactive ingredients: ammonium hydroxide, dibutyl sebacate, diethyl phthalate, ethylcellulose, FD&C Green No. 3, gelatin, hypromellose, maltodextrin, methacrylic acid copolymer Type A and B, oleic acid, polyethylene glycol, povidone, silicon dioxide, sodium lauryl sulfate, sugar spheres (which contain cornstarch and sucrose), talc and titanium dioxide, the 180 mg capsules also contain D&C Yellow No. 10.

In addition, the black imprinting ink contains black iron oxide, D&C Yellow No. 10 Aluminum Lake, FD&C Blue No. 1 Aluminum Lake, FD&C Blue No. 2 Aluminum Lake, FD&C Red No. 40 Aluminum Lake, propylene glycol and shellac glaze.

Clinical Pharmacology

Verapamil hydrochloride extended-release capsules are a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) which exert 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 verapamil hydrochloride extended-release capsules 240 mg were approximately 65% of those obtained with an 80 mg t.i.d. dose of the conventional immediate-release tablets, and the 24 hour post-dose concentrations were approximately 30% higher. At a total daily dose of 240 mg, verapamil hydrochloride extended-release capsules were 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 verapamil hydrochloride extended-release capsules 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 verapamil hydrochloride extended-release capsules 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 verapamil hydrochloride extended-release capsule. The verapamil hydrochloride extended-release 240 mg capsule when administered with food had a C_max of 77 ng/mL which occurred 9.0 hours after dosing, and an AUC(_0-inf) of 1387 ng•hr/mL. Verapamil hydrochloride extended-release capsules 240 mg under fasting conditions had a C_max of 77 ng/mL which occurred 9.8 hours after dosing, and an AUC(_0-inf) of 1541 ng•hr/mL.

The bioequivalence of verapamil hydrochloride extended-release capsules 240 mg, administered as the beads 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 C_max, T_max, and AUC(_0-inf) respectively. When the contents of the verapamil hydrochloride extended-release 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 (T_max) with verapamil hydrochloride extended-release capsules have 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 (t_1/2) 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 PRECAUTIONS: 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 (65-80 years) male and female subjects. Older subjects had significantly higher mean verapamil C_max, C_min 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_1/2 (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 mmHg 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 PRECAUTIONS: Drug Interactions.)

Pulmonary Function

Verapamil HCl does not induce broncho-constriction and hence, does not impair ventilatory function.

How Supplied / Storage and Handling

Verapamil Hydrochloride Extended-Release Capsules, USP are available containing 120 mg, 180 mg or 240 mg of verapamil hydrochloride, USP.

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

NDC 0378-6320-01
bottles of 100 capsules

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

NDC 0378-6380-01
bottles of 100 capsules

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

NDC 0378-6440-01
bottles of 100 capsules

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Brief digressions above 25°C while not detrimental, should be avoided.

Avoid excessive heat.

Protect from moisture.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Call your doctor for medical advice about side effects. You may report side effects to Mylan at 1-877-446-3679 (1-877-4-INFO-RX) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Manufactured for:
Mylan Pharmaceuticals Inc.
Morgantown, WV 26505 U.S.A.

Manufactured by:
Mylan Laboratories Limited
Hyderabad — 500 096, India

75080580

Revised: 6/2021
MX:CVERER:R1