VERAPAMIL: 9,320 Adverse Event Reports & Safety Profile

Verapamil Hydrochloride Extended-release Capsules (PM) is a calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist).

Verapamil Hydrochloride

Extended-release Capsules (PM) is available for oral administration as a 100 mg hard gelatin capsule (white opaque cap/amethyst body), a 200 mg hard gelatin capsule (amethyst opaque cap/amethyst body), and as a 300 mg hard gelatin capsule (lavender opaque cap/amethyst body). Verapamil is administered as a racemic mixture of the R and S enantiomers. The structural formulae of the verapamil HCl enantiomers are: C 27 H 38 N 2 O 4 ∙HCl M.W.=491.07 Chemical name: Benzeneacetonitrile, α-[3-[[2-(3,4-dimethoxyphenyl)ethyl]methylamino]propyl]- 3,4-dimethoxy-α-(1-methylethyl)-, monohydrochloride,(±)-. 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 structurally related to other cardioactive drugs. In addition to verapamil HCl the Verapamil Hydrochloride Extended-release Capsules (PM) capsule contains the following inactive ingredients: D&C Red #28, FD & C Blue #1, FD&C red #40, fumaric acid, gelatin, povidone, shellac, silicon dioxide, sodium lauryl sulfate, starch, sugar spheres, talc, and titanium dioxide.

System

Components and Performance: Verapamil Hydrochloride Extended-release Capsules (PM) uses the proprietary CODAS ® (Chronotherapeutic Oral Drug Absorption System) technology, which is designed for bedtime dosing, incorporating a 4 to 5-hour delay in drug delivery. The controlled-onset delivery system results in a maximum plasma concentration (C max ) of verapamil in the morning hours. These pellet filled capsules provide for extended-release of the drug in the gastrointestinal tract.

The Verapamil Hydrochloride

Extended-release Capsules (PM) formulation has been designed to initiate the release of verapamil 4-5 hours after ingestion. This delay is introduced by the level of non-enteric release-controlling polymer applied to drug loaded beads. The release-controlling polymer is a combination of water soluble and water insoluble polymers. As water from the gastrointestinal tract comes into contact with the polymer coated beads, the water soluble polymer slowly dissolves and the drug diffuses through the resulting pores in the coating. The water insoluble polymer continues to act as a barrier, maintaining the controlled release of the drug. The rate of release is essentially independent of pH, posture and food. Multiparticulate systems such as Verapamil Hydrochloride Extended-release Capsules (PM) have been shown to be independent of gastrointestinal motility.

Chemical

Structure

INDICATIONS AND USAGE 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 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) 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.

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 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) 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.

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. Do not crush or chew capsule contents; swallow capsule whole or sprinkle entire contents onto applesauce ( 2.2 , 17 ) Usual dosage: 200 mg once daily at bedtime; if inadequate response, titrate upward to 300 mg, then 400 mg once daily at bedtime ( 2.1 ) Initial dose of 100 mg once daily at bedtime in patients with renal or hepatic impairment, elderly or low-weight patients ( 2.1 )

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.

CONTRAINDICATIONS Verapamil hydrochloride injection is contraindicated in: Severe hypotension or cardiogenic shock. Second-or third-degree AV block (except in patients with a functioning artificial ventricular pacemaker). Sick sinus syndrome (except in patients with a functioning artificial ventricular pacemaker). Severe congestive heart failure (unless secondary to a supraventricular tachycardia amenable to verapamil hydrochloride therapy). Patients receiving intravenous beta-adrenergic blocking drugs (e.g., propranolol). Intravenous verapamil hydrochloride and intravenous beta-adrenergic blocking drugs should not be administered in close proximity to each other (within a few hours), since both may have a depressant effect on myocardial contractility and AV conduction. Patients with atrial flutter or atrial fibrillation and an accessory bypass tract (e.g., Wolff- Parkinson-White, Lown-Ganong-Levine syndromes) are at risk to develop ventricular tachyarrhythmia including ventricular fibrillation if verapamil hydrochloride is administered. Therefore, the use of verapamil hydrochloride in these patients is contraindicated. Ventricular tachycardia: Administration of intravenous verapamil hydrochloride to patients with wide-complex ventricular-tachycardia (QRS ≥ 0.12 sec) can result in marked hemodynamic deterioration and ventricular fibrillation. Proper pre-therapy diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative in the emergency room setting. Known hypersensitivity to verapamil hydrochloride.

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.

WARNINGS VERAPAMIL HYDROCHLORIDE INJECTION SHOULD BE GIVEN AS A SLOW INTRAVENOUS INJECTION OVER AT LEAST A TWO-MINUTE PERIOD OF TIME. (see DOSAGE AND ADMINISTRATION .) Hypotension: Verapamil hydrochloride injection often produces a decrease in blood pressure below baseline levels that is usually transient and asymptomatic but may result in dizziness. Systolic pressure less than 90 mm Hg and/or diastolic pressure less than 60 mm Hg was seen in 5% to 10% of patients in controlled U.S. trials in supraventricular tachycardia and in about 10% of the patients with atrial flutter/fibrillation. The incidence of symptomatic hypotension observed in studies conducted in the U.S. was approximately 1.5%. Three of the five symptomatic patients required intravenous pharmacologic treatment (norepinephrine bitartrate, metaraminol bitartrate, or 10% calcium gluconate). All recovered without sequelae.

Extreme

Bradycardia/Asystole: Verapamil hydrochloride affects the AV and SA nodes and rarely may produce second- or third-degree AV block, bradycardia, and, in extreme cases, asystole. This is more likely to occur in patients with a sick sinus syndrome (SA nodal disease), which is more common in older patients. Bradycardia associated with sick sinus syndrome was reported in 0.3% of the patients treated in controlled double-blind trials in the United States. The total incidence of bradycardia (ventricular rate less than 60 beats/min) was 1.2% in these studies. Asystole in patients other than those with sick sinus syndrome is usually of short duration (few seconds or less), with spontaneous return to AV nodal or normal sinus rhythm. If this does not occur promptly, appropriate treatment should be initiated immediately. (see ADVERSE REACTIONS: Suggested Treatment of Acute Cardiovascular Adverse Reactions .)

Heart

Failure: When heart failure is not severe or rate related, it should be controlled with digitalis glycosides and diuretics, as appropriate, before verapamil hydrochloride is used. In patients with moderately severe to severe cardiac dysfunction (pulmonary wedge pressure above 20 mm Hg, ejection fraction less than 30%), acute worsening of heart failure may be seen.

Concomitant Antiarrhythmic Therapy

Digitalis: Verapamil hydrochloride injection has been used concomitantly with digitalis preparations without the occurrence of serious adverse effects. However, since both drugs slow AV conduction, patients should be monitored for AV block or excessive bradycardia. Procainamide: Verapamil hydrochloride injection has been administered to a small number of patients receiving oral procainamide without the occurrence of serious adverse effects. Quinidine: Verapamil hydrochloride injection has been administered to a small number of patients receiving oral quinidine without the occurrence of serious adverse effects. However, three patients have been described in whom the combination resulted in an exaggerated hypotensive response presumably from the combined ability of both drugs to antagonize the effects of catecholamines on α-adrenergic receptors. Caution should therefore be used when employing this combination of drugs. Beta-Adrenergic Blocking Drugs: Verapamil hydrochloride injection has been administered to patients receiving oral beta-blockers without the development of serious adverse effects. However, since both drugs may depress myocardial contractility and AV conduction, the possibility of detrimental interactions should be considered. The concomitant administration of intravenous beta-blockers and intravenous verapamil hydrochloride has resulted in serious adverse reactions (see CONTRAINDICATIONS ) , especially in patients with severe cardiomyopathy, congestive heart failure, or recent myocardial infarction. Disopyramide: Until data on possible interactions between verapamil hydrochloride and all forms of disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil hydrochloride administration. Flecainide: A study in healthy volunteers showed that the concomitant administration of flecainide and verapamil hydrochloride may have additive effects reducing myocardial contractility, prolonging AV conduction, and prolonging repolarization.

Heart

Block: Verapamil hydrochloride prolongs AV conduction time. While high-degree AV block has not been observed in controlled clinical trials in the U.S., a low percentage (less than 0.5%) has been reported in the world literature. Development of second- or third-degree AV block or unifascicular, bifascicular, or trifascicular bundle branch block requires reduction in subsequent doses or discontinuation of verapamil hydrochloride and institution of appropriate therapy, if needed. (see ADVERSE REACTIONS: Suggested Treatment of Acute Cardiovascular Adverse Reactions .) Hepatic and Renal Failure: Significant hepatic and renal failure should not increase the effects of a single intravenous dose of verapamil hydrochloride but may prolong its duration. Repeated injections of verapamil hydrochloride injection in such patients may lead to accumulation and an excessive pharmacologic effect of the drug. There is no experience to guide use of multiple doses in such patients, and this generally should be avoided. If repeated injections are essential, blood pressure and PR interval should be closely monitored and smaller repeat doses should be utilized. Verapamil cannot be removed by hemodialysis.

Premature Ventricular

Contractions: During conversion to normal sinus rhythm, or marked reduction in ventricular rate, a few benign complexes of unusual appearance (sometimes resembling premature ventricular contractions) may be seen after treatment with verapamil hydrochloride. Similar complexes are seen during spontaneous conversion of supraventricular tachycardias, after D.C.-cardioversion and other pharmacologic therapy. These complexes appear to have no clinical significance. Duchenne's Muscular Dystrophy: Verapamil hydrochloride injection can precipitate respiratory muscle failure in these patients and should, therefore, be used with caution.

Increased Intracranial

Pressure: Verapamil hydrochloride injection has been seen to increase intracranial pressure in patients with supratentorial tumors at the time of anesthesia induction. Caution should be taken and appropriate monitoring performed.

PRECAUTIONS THE CONTENTS OF THE VERAPAMIL HYDROCHLORIDE SUSTAINED-RELEASE CAPSULES SHOULD NOT BE CRUSHED OR CHEWED. VERAPAMIL HYDROCHLORIDE SUSTAINED-RELEASE CAPSULES ARE TO BE SWALLOWED WHOLE OR THE ENTIRE CONTENTS OF THE CAPSULE SPRINKLED ONTO APPLESAUCE (see DOSAGE AND ADMINISTRATION ).

General

Use in Patients with Impaired Hepatic Function Since verapamil is highly metabolized by the liver, it should be administered cautiously to 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. Careful monitoring for abnormal prolongation of the PR interval or other signs of excessive pharmacologic effects (see OVERDOSAGE ) should be carried out. Use in Patients with 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. Use in Patients with Impaired Renal Function About 70% of an administered dose of verapamil is excreted as metabolites in the urine. Until further data are available, verapamil should be administered cautiously to patients with impaired renal function. These patients should be carefully monitored for abnormal prolongation of the PR interval or other signs of overdosage. (See OVERDOSAGE . ) Information for Patients When the sprinkle method of administration is prescribed, details of the proper technique should be explained to the patient. (See DOSAGE AND ADMINISTRATION .) Drug-Drug Interactions Drug Interactions: Effects of other drugs on verapamil pharmacokinetics: 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 while inducers of CYP3A4 (e.g., rifampin) have caused a lowering 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.

Ivabradine

Concurrent use of verapamil increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and verapamil. 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.

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 sustained-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 clearance has been reported when verapamil and metoprolol were administered together. A similar effect has not been observed when verapamil and atenolol are given together.

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.

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.

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. Patients receiving these combinations should be appropriately monitored. 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.

Antiarrhythmic Agents

Disopyramide: Until data on possible interactions between verapamil and disopyramide phosphate are obtained, disopyramide should not be administered within 48 hours before or 24 hours after verapamil administration. 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. Quinidine: In a small number of patients with hypertrophic cardiomyopathy (IHSS), concomitant use of verapamil and quinidine resulted in significant hypotension. Until further data are obtained, combined therapy of verapamil and quinidine in patients with hypertrophic cardiomyopathy should probably be avoided. 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. Nitrates: Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions. Alcohol: Verapamil has been found to significantly inhibit ethanol elimination resulting in elevated blood ethanol concentrations that may prolong the intoxicating effects of alcohol. (See CLINICAL PHARMACOLOGY - Pharmacokinetics and Metabolism .)

Other

Aspirin: In a few reported cases, coadministration of verapamil with aspirin has led to increased bleeding times greater than observed with aspirin alone. Cimetidine: The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.

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 PK of norverapamil. This increase in verapamil plasma concentration is not expected to have any clinical consequences. Lithium: Pharmacokinetic and pharmacodynamic interactions between oral verapamil and lithium have been reported. The former may result in a lowering of serum lithium levels in patients receiving chronic stable oral lithium therapy. The latter may result in an increased sensitivity to the effects of lithium. Patients receiving both drugs must be monitored carefully. Carbamazepine: Verapamil therapy may increase carbamazepine concentrations during combined therapy. This may produce carbamazepine side effects such as diplopia, headache, ataxia, or dizziness. Rifampin: Therapy with rifampin may markedly reduce oral verapamil bioavailability. Phenobarbital: Phenobarbital therapy may increase verapamil clearance. Cyclosporine: Verapamil therapy may increase serum levels of cyclosporine. Theophylline: Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

Inhalation

Anesthetics: Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, should be titrated carefully to avoid excessive cardiovascular depression.

Neuromuscular Blocking

Agents: Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly. Mammalian target of rapamycin (mTOR) inhibitors In a study of 25 healthy volunteers with co-administration of verapamil with sirolimus, whole blood sirolimus C max and AUC were increased 130% and 120%, respectively. Plasma S (-) verapamil C max and AUC were both increased 50%. Co-administration of verapamil with everolimus in 16 healthy volunteers increased the Cmax and AUC of everolimus by 130% and 250%, respectively. With concomitant use of mTOR inhibitors (e.g., sirolimus, temsirolimus, and everolimus) and verapamil, consider appropriate dose reductions of both medications. Carcinogenesis, Mutagenesis, Impairment of Fertility An 18-month toxicity study in rats, at a low multiple (6 fold) of the maximum recommended human dose, and not the maximum tolerated dose, did not suggest a tumorigenic potential. There was no evidence of a carcinogenic potential of verapamil administered in the diet of rats for two years at doses of 10, 35 and 120 mg/kg per day or approximately 1x, 3.5x and 12x, respectively, the maximum recommended human daily dose (480 mg per day or 9.6 mg/kg/day). Verapamil was not mutagenic in the Ames test in 5 test strains at 3 mg per plate, with or without metabolic activation. Studies in female rats at daily dietary doses up to 5.5 times (55 mg/kg/day) the maximum recommended human dose did not show impaired fertility. Effects on male fertility have not been determined.

Pregnancy Pregnancy

Category C . Reproduction studies have been performed in rabbits and rats at oral doses up to 1.5 (15 mg/kg/day) and 6 (60 mg/kg/day) times the maximum recommended human 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. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Verapamil crosses the placental barrier and can be detected in umbilical vein blood at delivery. 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 HCl in Europe in the treatment of cardiac side effects of beta-adrenergic agonist agents used to treat premature labor.

Nursing Mothers

Verapamil is excreted in human milk. Because of the potential for adverse reactions in nursing infants from verapamil, nursing should be discontinued while verapamil is administered.

Pediatric Use

Safety and efficacy of verapamil in children below the age of 18 years have not been established.

Geriatric Use

Clinical studies of verapamil did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy. Aging may affect the pharmacokinetics of verapamil. Elimination half-life may be prolonged in the elderly (see CLINICAL PHARMACOLOGY, Pharmacokinetics and Metabolism ). 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 PRECAUTIONS, General ). In general, lower initial doses of verapamil hydrochloride sustained-release capsules may be warranted in the elderly (see DOSAGE AND ADMINISTRATION ).

Animal

Pharmacology and/or Animal Toxicology 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 the rat. Development of cataracts due to verapamil has not been reported in man.

INTERACTIONS 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.

7.17 Lithium Increased sensitivity to the effects of lithium (neurotoxicity) has been reported during concomitant verapamil-lithium therapy with either no change or an increase in serum lithium levels. However, the addition of verapamil has also resulted in the lowering of serum lithium levels in patients receiving chronic stable oral lithium. Patients receiving both drugs must be monitored carefully.

7.18 Inhalation Anesthetics Animal experiments have shown that inhalation anesthetics depress cardiovascular activity by decreasing the inward movement of calcium ions. When used concomitantly, inhalation anesthetics and calcium antagonists, such as verapamil, titrate slowly to avoid excessive cardiovascular depression.

7.19 Neuromuscular Blocking Agents Clinical data and animal studies suggest that verapamil may potentiate the activity of neuromuscular blocking agents (curare-like and depolarizing). It may be necessary to decrease the dose of verapamil and/or the dose of the neuromuscular blocking agent when the drugs are used concomitantly.

7.20 Phenobarbital Phenobarbital therapy may increase verapamil clearance.

7.21 Rifampin Therapy with rifampin may markedly reduce oral verapamil bioavailability.

7.22 Theophylline Verapamil may inhibit the clearance and increase the plasma levels of theophylline.

7.23 Cimetidine The interaction between cimetidine and chronically administered verapamil has not been studied. Variable results on clearance have been obtained in acute studies of healthy volunteers; clearance of verapamil was either reduced or unchanged.

7.24 Nitrates Verapamil has been given concomitantly with short- and long-acting nitrates without any undesirable drug interactions. The pharmacologic profile of both drugs and the clinical experience suggest beneficial interactions.

7.25 Mammalian Target of Rapamycin (mTOR) Inhibitors In a study of 25 healthy volunteers with co-administration of verapamil with sirolimus, whole blood sirolimus C max and AUC were increased 130% and 120%, respectively. Plasma S(-) verapamil C max and AUC were both increased 50%. Co-administration of verapamil with everolimus in 16 healthy volunteers increased the C max and AUC of everolimus by 130% and 250%, respectively. With concomitant use of mTOR inhibitors (e.g., sirolimus, temsirolimus, and everolimus) and verapamil, consider appropriate dose reductions of both medications.