Verapamil Hydrochloride: Package Insert and Label Information

VERAPAMIL HYDROCHLORIDE- verapamil hydrochloride capsule, extended release
Lannett Company, Inc.

1 INDICATIONS AND USAGE

Verapamil Hydrochloride Extended-release Capsules (PM) for oral use 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.

2 DOSAGE AND ADMINISTRATION

THE CONTENTS OF THE Verapamil Hydrochloride Extended-release Capsules (PM) CAPSULE SHOULD NOT BE CRUSHED OR CHEWED. Verapamil Hydrochloride Extended-release Capsules (PM) CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE.

2.1 Essential Hypertension

Administer Verapamil Hydrochloride Extended-release Capsules (PM) once daily at bedtime. Clinical trials studied doses of 100 mg, 200 mg, 300 mg, and 400 mg. The usual daily dose of extended-release Verapamil Hydrochloride Extended-release Capsules (PM) in clinical trials has been 200 mg given by mouth once daily at bedtime. In rare instances, initial doses of 100 mg a day may be warranted in patients who have an increased response to verapamil [e.g. patients with impaired renal function, impaired hepatic function, elderly, low-weight patients, etc. (see Use in Specific Populations (8.5, 8.6, 8.7))]. Base upward titration on therapeutic efficacy and safety evaluated approximately 24 hours after dosing. The antihypertensive effects of Verapamil Hydrochloride Extended-release Capsules (PM) are evident within the first week of therapy.

If an adequate response is not obtained with 200 mg of Verapamil Hydrochloride Extended-release Capsules (PM), the dose may be titrated upward in the following manner:

a) 300 mg each evening b) 400 mg each evening (2 × 200 mg)

When Verapamil Hydrochloride Extended-release Capsules (PM) 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 Hydrochloride Extended-release Capsules (PM), would be just prior to bedtime.

2.2 Sprinkling the Capsule Contents on Food

Verapamil Hydrochloride Extended-release Capsules (PM) capsules may also be administered by carefully opening the capsule and sprinkling the pellets onto one tablespoonful of applesauce. Swallow the applesauce immediately without chewing and follow 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. Use any pellet/applesauce mixture immediately and do not store for future use. Absorption of the pellets sprinkled onto other foods has not been tested. This method of administration may be beneficial for patients who have difficulty swallowing whole capsules. Subdividing the contents of a Verapamil Hydrochloride Extended-release Capsules (PM) capsule is not recommended.

3 DOSAGE FORMS AND STRENGTHS

Extended-release capsules controlled onset: 100 mg, 200 mg, and 300 mg.

100 mg: white opaque cap and amethyst body imprinted KU/485 100 mg.

200 mg: amethyst opaque cap and amethyst body imprinted KU/486 200 mg.

300 mg: lavender opaque cap and amethyst body imprinted KU/487 300 mg.

4 CONTRAINDICATIONS

Verapamil is contraindicated in:

  • Severe left ventricular dysfunction [see Warnings and Precautions (5.1) ].
  • 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 and Precautions (5.4) ].

5 WARNINGS AND PRECAUTIONS

5.1 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 previous clinical experience with 4,954 patients primarily with immediate-release verapamil, 87 (1.8%) developed congestive heart failure or pulmonary edema. Avoid verapamil 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 Drug Interactions (7.4) ]. Control patients with milder ventricular dysfunction, if possible, with optimum doses of digitalis and/or diuretics before verapamil treatment is started [see Drug Interactions (7.5) ].

5.2 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 hypertensive patients, decreases in blood pressure below normal are unusual. The incidence of hypotension observed in 4,954 patients enrolled in clinical trials of other verapamil formulations was 2.5% [see Adverse Reactions (6.1) ]. In clinical studies of Verapamil Hydrochloride Extended-release Capsules (PM), 1.7% of the patients developed significant hypotension. Tilt table testing (60 degrees) was not able to induce orthostatic hypotension.

5.3 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 elevations of SGOT, SGPT, and alkaline phosphatase. Periodic monitoring of liver function in patients receiving verapamil is therefore prudent.

5.4 Accessory Bypass Tract (Wolff-Parkinson-White or Lown-Ganong-Levine)

Some patients with paroxysmal and/or chronic atrial flutter or atrial fibrillation 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 (4) ]. Treatment is usually DC-cardioversion. Cardioversion has been used safely and effectively after oral verapamil.

5.5 Atrioventricular Block

The effect of verapamil on AV conduction and the SA node may lead to 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 [see Adverse Reactions (6.1) ].

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 and institution of appropriate therapy depending upon the clinical situation.

5.6 Patients with Hypertrophic Cardiomyopathy

In 120 patients with hypertrophic cardiomyopathy, idiopathic hypertrophic subaortic stenosis (IHSS) (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 history of left ventricular dysfunction. Eight other patients had pulmonary edema and/or severe hypotension; abnormally high (over 20 mm Hg) pulmonary capillary wedge pressure and a marked left ventricular outflow obstruction were present in most of these patients. Concomitant administration of quinidine [see Drug Interactions (7.10) ] 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% [see Adverse Reactions (6) ]. 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 have to be discontinued.

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical trials does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Serious adverse reactions are uncommon when verapamil therapy is initiated with upward dose titration within the recommended single and total daily dose. See Warnings and Precautions (5.1, 5.2, 5.3, 5.4, 5.5) 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 (Table 1) to orally administered Verapamil Hydrochloride Extended-release Capsules (PM) occurred at rates of 2.0% or greater or occurred at lower rates but appeared to be drug-related in clinical trials in hypertension.

Table 1. Adverse Events Occurring in ≥ 2% of Verapamil Hydrochloride Extended-release Capsules (PM) Patients in Placebo- Controlled Clinical Trials
All Doses StudiedN = 297% PlaceboN = 116% All Doses StudiedN = 297% PlaceboN = 116%
*
Infection, primarily upper respiratory infection (URI) and unrelated to study medication. Constipation was typically mild and easily manageable. At the usual once-daily dose of 200 mg, the observed incidence of constipation was 3.9%.
Headache 12.1 11.2 Dyspepsia 2.7 1.7
Infection 12.1* 6.9 Rhinitis 2.7 2.6
Constipation 8.8* 0.9 Diarrhea 2.4 1.7
Flu Syndrome 3.7 2.6 Pain 2.4 1.7
Peripheral edema 3.7 0.9 Edema 1.7 0.0
Dizziness 3.0 0.9 Nausea 1.7 0.0
Pharyngitis 3.0 2.6 Accidental Injury 1.5 0.0
Sinusitis 3.0 2.6

In previous experience with other formulations of verapamil (N=4,954) the following reactions (Table 2) have 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 Events Occurring in >1% (or lower rates and clearly drug related) of Patients with Other Verapamil Formulations
Constipation 7.3% Fatigue 1.7%
Dizziness 3.3% Bradycardia (HR<50/min) 1.4%
Nausea 2.7% Rash 1.2%
Hypotension 2.5% AV block (total 1°, 2°, 3°) 1.2%
Headache 2.2% AV block (2° and 3°) 0.8%
Edema 1.9% Flushing 0.6%
CHF/Pulmonary Edema 1.8%

In clinical trials related to the control of ventricular response in patients taking digoxin 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.

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