Verapamil Hydrochloride

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 )

Extended-release capsules controlled onset: 100 mg 100 mg: white opaque cap and amethyst body imprinted KU/485 100 mg.

• Extended-release capsules controlled-onset: 100 mg ( 3 )

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 )] .

• Severe left ventricular dysfunction ( 4 )
• Hypotension (<90 mmHg systolic pressure) or cardiogenic shock ( 4 )
• Sick sinus syndrome (except in patients with pacemaker) ( 4 )
• 2nd- or 3rd-degree AV block (except in patients with pacemaker) ( 4 )
• Atrial flutter or atrial fibrillation and an accessory bypass tract ( 4 )

Congestive heart failure or pulmonary edema may develop ( 5.1 ) Hypotension/dizziness may occur ( 5.2 ) Elevated transaminases have occurred; monitor liver function ( 5.3 ) Ventricular fibrillation has occurred in patients with atrial flutter or atrial fibrillation and an accessory bypass tract ( 5.4 ) Reduce dose or discontinue therapy if marked first-degree AV block or progression to second- or third-degree AV block occurs ( 5.5 ) Sinus bradycardia, pulmonary edema, severe hypotension, second-degree AV block, sinus arrest, and death occurred in patients with hypertrophic cardiomyopathy ( 5.6 )

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.

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.

CYP3A4 inhibitors increase verapamil levels ( 7.1 ) CYP3A4 inducers decrease verapamil levels ( 7.1 ) If simvastatin is co-administered with verapamil, do not exceed doses greater than 10 mg daily of simvastatin ( 7.2 ) If lovastatin is co-administered with verapamil, do not exceed doses greater than 40 mg daily of lovastatin ( 7.2 ) Grapefruit juice may significantly increase verapamil levels ( 7.3 ) Beta blockers: reports of excess bradycardia and AV block, including complete heart block; monitor closely ( 7.4 ) Digoxin levels can increase by 50 to 75%; reduce digoxin dose ( 7.5 ) Alcohol elimination inhibited resulting in elevated ethanol levels ( 7.6 ) 7.1 CYP3A4 Inhibitors and Inducers In vitro metabolic studies indicate that verapamil is metabolized by cytochrome P450, CYP3A4, CYP1A2, and CYP2C. Clinically significant interactions have been reported with inhibitors of CYP3A4 (e.g., erythromycin, ritonavir) causing elevation of plasma levels of verapamil. Hypotension, bradyarrhythmias, and lactic acidosis have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics. Inducers of CYP3A4 (e.g., rifampin) have caused a lowering of plasma levels of verapamil. Ivabradine Concurrent use of verapamil increases exposure to ivabradine and may exacerbate bradycardia and conductions disturbances. Avoid concomitant use of ivabradine and verapamil. 7.2 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.

7.3 Grapefruit Juice Grapefruit juice may significantly increase concentrations of verapamil. Grapefruit juice given to nine healthy volunteers increased S- and R- verapamil AUC 0-12 by 36% and 28%, respectively. Steady state C max and C min of S-verapamil increased by 57% and 16.7%, respectively with grapefruit juice compared to control. Similarly, C max and C min of R-verapamil increased by 40% and 13%, respectively. Grapefruit juice did not affect half-life, nor was there a significant change in AUC 0-12 ratio R/S compared to control. Grapefruit juice did not cause a significant difference in the pharmacokinetics of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences.

7.4 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 excess bradycardia and AV block, including complete heart block, when the combination has been used for the treatment of hypertension. For hypertensive patients, the risk 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.

7.5 Digitalis Consider reducing digoxin dose when verapamil and digoxin are to be given together. Monitor digoxin level periodically during therapy. 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 pharmacokinetics is magnified. Verapamil may reduce total body clearance and extrarenal clearance of digoxin by 27% and 29%, respectively. If digoxin toxicity is suspected, suspend or discontinue digoxin therapy. In previous clinical trials with other verapamil formulations related to the control of ventricular response in patients taking digoxin who had atrial fibrillation or atrial flutter, ventricular rates below 50/min at rest occurred in 15% of patients, and asymptomatic hypotension occurred in 5% of patients.

7.6 Alcohol Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol.

7.7 Clonidine Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with verapamil. Monitor heart rate in patients receiving concomitant verapamil and clonidine.

7.8 Telithromycin Hypotension and bradyarrhythmias have been observed in patients receiving concurrent telithromycin, an antibiotic in the ketolide class of antibiotics.

7.9 Antineoplastic Agents Verapamil can increase doxorubicin levels. The absorption of verapamil can be reduced by the cyclophosphamide, oncovin, procarbazine, prednisone (COPP) and the vindesine, adriamycin, cisplatin (VAC) cytotoxic drug regimens. Concomitant administration of R verapamil can decrease the clearance of paclitaxel.

7.10 Quinidine In a small number of patients with hypertrophic cardiomyopathy, concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, avoid combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy. The electrophysiological effects of quinidine and verapamil on AV conduction were studied in 8 patients. Verapamil significantly counteracted the effects of quinidine on AV conduction. There has been a report of increased quinidine levels during verapamil therapy.

7.11 Aspirin In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone.

7.12 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. Monitor patients receiving these combinations appropriately. Concomitant use of agents that attenuate alpha-adrenergic function with verapamil may result in 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.

7.13 Disopyramide Until data on possible interactions between verapamil and disopyramide are obtained, do not administer disopyramide within 48 hours before or 24 hours after verapamil administration.

7.14 Flecainide A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil may have additive effects on myocardial contractility, AV conduction, and repolarization. Concomitant therapy with flecainide and verapamil may result in additive negative inotropic effect and prolongation of atrioventricular conduction.

7.15 Carbamazepine Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness.

7.16 Cyclosporine Verapamil therapy may increase serum levels of cyclosporine. […]

Use during pregnancy only if potential benefit justifies the potential risk to the fetus ( 8.1 ) Discontinue nursing while verapamil is administered ( 8.3 ) Safety and effectiveness in pediatric patients have not been established ( 8.4 )

8.1 Pregnancy Pregnancy Category C. Reproduction studies have been performed in rabbits and rats at oral doses up to 1.9 (15 mg/kg/day) and 7.5 (60 mg/kg/day) times the human oral daily dose, respectively, and have revealed no evidence of teratogenicity. In the rat, however, this multiple of the human dose was embryocidal and retarded fetal growth and development, probably because of adverse maternal effects reflected in reduced weight gains of the dams. This oral dose has also been shown to cause hypotension in rats. There are no adequate and well-controlled studies in pregnant women. Verapamil should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery.

8.2 Labor and Delivery It is not known whether the use of verapamil during labor or delivery has immediate or delayed adverse effects on the fetus, or whether it prolongs the duration of labor or increases the need for forceps delivery or other obstetric intervention. Such adverse experiences have not been reported in the literature, despite a long history of use of verapamil in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

8.3 Nursing Mothers Verapamil is excreted into human milk. In case studies where verapamil concentration in human milk was calculated, the nursing infant doses ranged from less than 0.01% to 0.1% of the mother's verapamil dose. Consider possible infant exposure when verapamil is administered to a nursing woman.

8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use Clinical studies of Verapamil Hydrochloride Extended-release Capsules (PM) were not adequate to determine if subjects aged 65 or over respond differently from younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients; however, greater sensitivity to Verapamil Hydrochloride Extended-release Capsules (PM) by some older individuals cannot be ruled out. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly [see Clinical Pharmacology ( 12.3 )]. Verapamil is highly metabolized by the liver, and about 70% of the administered dose is excreted as metabolites in the urine. Clinical circumstances, some of which may be more common in the elderly, such as hepatic or renal impairment, should be considered [see Use in Specific Populations ( 8.6 , 8.7 )]. In general, lower initial doses of Verapamil Hydrochloride Extended-release Capsules (PM) may be warranted in the elderly [see Dosage and Administration ( 2.1 )].

8.6 Impaired Hepatic Function Since verapamil is highly metabolized by the liver, consider lower dosages and closely monitor responses to the drug in patients with impaired hepatic function. Severe liver dysfunction prolongs the elimination half-life of immediate-release verapamil to about 14 to 16 hours; hence, approximately 30% of the dose given to patients with normal liver function should be administered to these patients. Monitor for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects [see Overdosage (10) ].

8.7 Impaired Renal Function 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, monitor these patients for abnormal prolongation of the PR interval or other signs of overdosage [see Overdosage (10) ].

8.8 Attenuated (decreased) Neuromuscular Transmission It has been reported that verapamil decreases neuromuscular transmission in patients with Duchenne's muscular dystrophy, and that verapamil prolongs recovery from the neuromuscular blocking agent vecuronium and causes a worsening of myasthenia gravis. It may be necessary to decrease the dosage of verapamil when it is administered to patients with attenuated neuromuscular transmission.