Verapamil Hydrochloride

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. Verapamil Hydrochloride Extended-release Capsules (PM) is a calcium channel blocker 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. ( 1 )

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥ 3% and more common than in patients treated with placebo) are headache, infection, constipation, flu syndrome, peripheral edema, dizziness, pharyngitis, and sinusitis ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. at 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 Studied N = 297 % Placebo N = 116 % All Doses Studied N = 297 % Placebo N = 116 % 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 * 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%. 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. 6.2 Open Trials / Postmarketing Experience The following reactions, reported with orally administered verapamil in 2.0% or less of patients, occurred under conditions (open verapamil trials, postmarketing experience [reactions added since the initial US approval of Verapamil Hydrochloride Extended-release Capsules (PM) in 1998 are marked with an asterisk]) where a causal relationship is uncertain; they are listed to alert the physician to a possible relationship: Cardiovascular : angina pectoris, atrioventricular dissociation, ECG Abnormal*, chest pain, claudication, hypertension*, myocardial infarction, palpitations, purpura (vasculitis), syncope. Digestive System : diarrhea, dry mouth, elevated liver enzymes* [see Warnings and Precautions ( 5.3 )] , 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, macules, sweating, urticaria, Stevens-Johnson syndrome, erythema multiforme. Special Senses : blurred vision, tinnitus. Urogenital : gynecomastia, galactorrhea/hyperprolactinemia, impotence, increased urination, spotty menstruation. Other : allergy aggravated, asthenia*. 6.3 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, apply the appropriate emergency measures 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, use alpha-adrenergic agents (phenylephrine HCl, metaraminol bitartrate, or methoxamine HCl) to maintain blood pressure, and isoproterenol and avoid norepinephrine. If further support is necessary, inotropic agents (dopamine HCl or dobutamine HCl) may be administered. Actual treatment and dosage depends on the severity of the clinical situation and the judgment and experience of the treating physician.