Diltiazem Hydrochloride (1069)

CATEGORIES, DRUG CLASSES, BRAND NAMES & COST OF THERAPY

Injectable forms of diltiazem are contraindicated in:

• Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker.

• Patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker.

• Patients with severe hypotension or cardiogenic shock.

• Patients who have demonstrated hypersensitivity to the drug.

• IV diltiazem and IV beta-blockers should not be administered together or in close proximity (within a few hours).

• Patients with atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in WPW syndrome or short PR syndrome. As with other agents which slow AV nodal conduction and do not prolong the refractoriness of the accessory pathway (e.g.,verapamil, digoxin), in rare instances patients in atrial fibrillation or atrial flutter associated with an accessory bypass tract may experience a potentially life-threatening increase in heart rate accompanied by hypotension when treated with injectable forms of diltiazem. As such, the initial use of injectableforms of diltiazem should be, if possible, in a setting where monitoring and resuscitation capabilities, including DC cardioversion/defibrillation, are present (see OVERDOSAGE). Once familiarity of the patient's response is established, use in an office setting may be acceptable.

• Patients with ventricular tachycardia. Administration of other calcium channel blockers to patients with wide complex tachycardia (QRS ≥0.12 seconds) has resulted in hemodynamic deterioration and ventricular fibrillation. It is important that an accurate pretreatment diagnosis distinguishwide complex QRS tachycardia of supraventricular origin from that of ventricular origin prior to administration of injectable forms of diltiazem.

• In newborns, due to the presence of benzyl alcohol (Cardizem Lyo-Ject syringe only).

Cardiac Conduction

Diltiazem prolongs AV nodal conduction and refractoriness that may rarely result in second- or third-degree AV block in sinus rhythm. Concomitant use of diltiazem with agents known to affect cardiac conduction may result in additive effects (see DRUG INTERACTIONS). If high-degreeAV block occurs in sinus rhythm, IV diltiazem should be discontinued and appropriate supportive measures instituted (see OVERDOSAGE).

Congestive Heart Failure

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function and in patients with a compromised myocardium, such as severe CHF, acute MI, and hypertrophic cardiomyopathy, have not shown a reduction in cardiacindex nor consistent negative effects on contractility (dp/dt). Administration of oral diltiazem in patients with acute myocardial infarction and pulmonary congestion documented by x-ray on admission is contraindicated. Experience with the use of Cardizem injectable in patients with impaired ventricular functionis limited. Caution should be exercised when using the drug in such patients.

Hypotension

Decreases in blood pressure associated with Cardizem injectable therapy may occasionally result in symptomatic hypotension (3.2%). The use of IV diltiazem for control of ventricular response in patients with supraventricular arrhythmias should be undertaken with caution when the patient is compromisedhemodynamically. In addition, caution should be used in patients taking other drugs that decrease peripheral resistance, intravascular volume, myocardial contractility or conduction.

Acute Hepatic Injury

In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted following oral diltiazem. Therefore, the potential for acute hepatic injury exists following administration of IV diltiazem.

Ventricular Premature Beats (VPBs)

VPBs may be present on conversion of PSVT to sinus rhythm with Cardizem injectable. These VPBs are transient, are typically considered to be benign, and appear to have no clinical significance. Similar ventricular complexes have been noted during cardioversion, other pharmacologic therapy, and duringspontaneous conversion of PSVT to sinus rhythm.

General

Cardizem is extensively metabolized by the liver and excreted by the kidneys and in bile. The drug should be used with caution in patients with impaired renal or hepatic function (see WARNINGS). High IV dosages (4.5 mg/kg tid) administered to dogs resulted in significantbradycardia and alterations in AV conduction. In subacute and chronic dog and rat studies designed to produce toxicity, high oral doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changesin the liver, which were reversible when the drug was discontinued. In dogs, oral doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatologic events progressing to erythema multiforme and/or exfoliative dermatitis have been infrequently reported following oral diltiazem. Therefore, the potential for these dermatologic reactions exists following exposure to IV diltiazem. Should a dermatologic reaction persist, the drug shouldbe discontinued.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A 24 month study in rats at oral dosage levels of up to 100 mg/kg/day and a 21 month study in mice at oral dosage levels of up to 30 mg/kg/day showed no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivoin mammalian cell assays or in vitro in bacteria. No evidence of impaired fertility was observed in a study performed in male and female rats at oral dosages of up to 100 mg/kg/day.

Pregnancy Category C

Reproduction studies have been conducted in mice, rats, and rabbits.

Administration of oral doses ranging from 5-10 times greater (on a mg/kg basis) than the daily recommended oral antianginal therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studiesthere was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human oral antianginal dose or greater.

There are no well-controlled studies in pregnant women; therefore, use Cardizem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Diltiazem is excreted in human milk. One report with oral diltiazem suggests that concentrations in breast milk may approximate serum levels. If use of Cardizem is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Due to potential for additive effects, caution is warranted in patients receiving Cardizem injectable, Cardizem Lyo-Ject syringe, or Cardizem Monovial concomitantly with other agent(s) known to affect cardiac contractility and/or SA or AV node conduction (see WARNINGS).

As with all drugs, care should be exercised when treating patients with multiple medications. Cardizem undergoes extensive metabolism by the cytochrome P-450 mixed function oxidase system. Although specific pharmacokinetic drug-drug interaction studies have not been conducted with single IV injectionor constant rate IV infusion, coadministration of injectable diltiazem with other agents which primarily undergo the same route of biotransformation may result in competitive inhibition of metabolism.

Digitalis

IV diltiazem has been administered to patients receiving either IV or oral digitalis therapy. The combination of the two drugs was well tolerated without serious adverse effects. However, since both drugs affect AV nodal conduction, patients should be monitored for excessive slowing of the heart rateand/or AV block.

Beta-Blockers

IV diltiazem has been administered to patients on chronic oral beta-blocker therapy. The combination of the two drugs was generally well tolerated without serious adverse effects. If IV diltiazem is administered to patients receiving chronic oral beta-blocker therapy, the possibility for bradycardia,AV block, and/or depression of contractility should be considered (see CONTRAINDICATIONS). Oral administration of diltiazem with propranolol in 5 normal volunteers resulted in increased propranolol levels in all subjects and bioavailabilityof propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by diltiazem.

Anesthetics

The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.

Cyclosporine

A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15-48% was necessary to maintain cyclosporine trough concentrationssimilar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted or discontinued.

The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Carbamazepine

Concomitant administration of oral diltiazem with carbamazepine has been reported to result in elevated plasma levels of carbamazepine (by 40-72%), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitoredfor a potential drug interaction.

Cardizem CD Capsules

The therapeutic effects of Cardizem CD are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Mechanism of Action

Hypertension

Cardizem CD produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension; thus hypertensive individuals experience an antihypertensiveeffect, whereas there is only a modest fall in blood pressure in normotensives.

Angina

Cardizem CD has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal work loads. Diltiazem has been shown to be a potent dilator ofcoronary arteries, both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasm are inhibited by diltiazem.

In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscleand dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic bloodpressure and decreases in peripheral resistance.

Hemodynamic and Electrophysiologic Effects

Like other calcium channel antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses. In man, diltiazem prevents spontaneousand ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product for any given workload. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end diastolic pressure have not been affected. Such data have no predictive value with respect to effects in patientswith poor ventricular function, and increased heart failure has been reported in patients with preexisting impairment of ventricular function. There are as yet few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Resting heart rate is usually slightly reducedby diltiazem.

In hypertensive patients, Cardizem CD produces antihypertensive effects both in the supine and standing positions. In a double-blind, parallel, dose-response study utilizing doses ranging from 90 to 540 mg once daily, Cardizem CD lowered supine diastolic blood pressure in an apparent linear manner overthe entire dose range studied. The changes in diastolic blood pressure, measured at trough, for placebo, 90 mg, 180 mg, 360 mg, and 540 mg were -2.9, -4.5, -6.1, -95, and -10.5 mm Hg, respectively. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardiais associated with the chronic antihypertensive effects. Cardizem CD decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievablesystolic pressure is usually reduced. Chronic therapy with Cardizem CD produces no change or an increase in plasma catecholamines. No increased activity of the rennin-angiotensin-aldosterone axis has been observed. Cardizem CD reduces the renal and peripheral effects of angiotensin II. Hypertensive animalmodels respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio.

In a double-blind, parallel dose-response study of doses from 60-480 mg once daily, Cardizem CD increased time to termination of exercise in a linear manner over the entire dose range studied. The improvement in time to termination of exercise utilizing a Bruce exercise protocol, measured at trough,for placebo, 60 mg, 120 mg, 240 mg, 360 mg, and 480 mg was 29, 40, 56, 51, 69, and 68 seconds, respectively. As doses of Cardizem CD were increased, overall angina frequency was decreased. Cardizem CD, 180 mg once daily, or placebo was administered in a double-blind study to patients receiving concomitanttreatment with long-acting nitrates and/or beta-blockers. A significant increase in time to termination of exercise and a significant decrease in overall angina frequency was observed. In this trial the overall frequency of adverse events in the Cardizem CD treatment group was the same as the placebo group.IV diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of 300 mg of Cardizem in 6 normal volunteers, the average maximum PR prolongation was 14% with no instances of greater than first-degreeAV block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of Cardizem to patients in doses of up to 540 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation. (See WARNINGS, Cardizem CD Capsules.)

Pharmacokinetics and Metabolism

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to IV administration) of about 40%. Cardizem undergoes extensive metabolism in which only 2-4% of the unchanged drug appears in the urine. Drugs whichinduce or inhibit hepatic microsomal enzymes may alter diltiazem disposition.

Total radioactivity measurement following short IV administration in healthy volunteers suggests the presence of other unidentified metabolites, which attain higher concentrations than those of diltiazem and are more slowly eliminated; half-life of total radioactivity is about 20 hours compared to 2-5hours for diltiazem.

In vitro binding studies show Cardizem is 70-80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown Cardizem binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide,phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0-4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10-20% of the parent drug and is 25-50% as potent as a coronary vasodilatoras diltiazem. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50-200 ng/ml. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose. A study that compared patients with normal hepatic function to patients with cirrhosisfound an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. A single study in 9 patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function.

Cardizem CD Capsules

When compared to a regimen of Cardizem tablets at steady-state, more than 95% of drug is absorbed from the Cardizem CD formulation. A single 360-mg dose of the capsule results in detectable plasma levels within 2 hours and peak plasma levels between 10 and 14 hours; absorption occurs throughout thedosing interval. When Cardizem CD was coadministered with a high fat content breakfast, the extent of diltiazem absorption was not affected. Dose-dumping does not occur. The apparent elimination half-life after single or multiple dosing is 5-8 hours. A departure from linearity similar to that seen with Cardizemtablets and Cardizem SR capsules is observed. As the dose of Cardizem CD capsules is increased from a daily dose of 120-240 mg, there is an increase in the area-under-the-curve of 2.7 times. When the dose is increased from 240-360 mg there is an increase in the area-under-the-curve of 1.6 times.

Cardizem Direct Compression Tablets

The therapeutic effects of Cardizem are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Mechanism of Action

Although precise mechanisms of its antianginal actions are still being delineated, Cardizem is believed to act in the following ways:

Angina due to coronary artery spasm: Cardizem has been shown to be a potent dilator of coronary arteries both epicardial and subendocardial. Spontaneous and ergonovine-induced coronary artery spasms are inhibited by Cardizem.

Exertional angina: Cardizem has been shown to produce increases in exercise tolerance, probably due to its ability to reduce myocardial oxygen demand. This is accomplished via reductions in heart rate and systemic blood pressure at submaximal and maximal exercise workloads.

In animal models, diltiazem interferes with the slow inward (depolarizing) current in excitable tissue. It causes excitation-contraction uncoupling in various myocardial tissues without changes in the configuration of the action potential. Diltiazem produces relaxation of coronary vascular smooth muscleand dilation of both large and small coronary arteries at drug levels which cause little or no negative inotropic effect. The resultant increases in coronary blood flow (epicardial and subendocardial) occur in ischemic and nonischemic models and are accompanied by dose-dependent decreases in systemic bloodpressure and decreases in peripheral resistance.

Hemodynamic and Electrophysiologic Effects

Like other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.

In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-blood pressure product forany given work load. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end-diastolic pressure have not been affected. There are as yet few data on the interaction of diltiazemand beta-blockers. Resting heart rate is usually unchanged or slightly reduced by diltiazem.

IV diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of 300 mg of Cardizem in 6 normal volunteers, the average maximum PR prolongation was 14% with no instances of greater thanfirst-degree AV block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of Cardizem in doses of up to 240 mg/day has resulted in small increases in PR interval, but has not usually produced abnormal prolongation.

Pharmacokinetics and Metabolism

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to IV dosing) of about 40%. Cardizem undergoes extensive metabolism in which 2-4% of the unchanged drug appears in the urine. In vitro binding studies show Cardizem is 70-80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown Cardizem binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylicacid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0-4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10-20% of the parent drug and is 25-50% as potent a coronary vasodilator as diltiazem. Minimum therapeutic plasmalevels of Cardizem appear to be in the range of 50-200 ng/ml. There is a departure from linearity when dose strengths are increased. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69% increase in AUC (area-under-the-plasma concentrationversus time curve) in the hepatically impaired patients. A single study in 9 patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem as compared to patients with normal renal function.

Cardizem Direct Compression Tablets

Diltiazem is absorbed from the tablet formulation to about 98% of a reference solution. Single oral doses of 30-120 mg of Cardizem direct compression tablets result in detectable plasma levels within 30-60 minutes and peak plasma levels 2-4 hours after drug administration. As the dose of Cardizem directcompression tablets is increased from a daily dose of 120 mg (30 mg qid) to 240 mg (60 mg qid) daily, there is an increase in area-under-the curve of 2.3 times. When the dose is increased from 240-360 mg daily, there is an increase in area-under-the-curve of 1.8 times.

Cardizem LA Extended Release Tablets

The therapeutic effects of diltiazem are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Mechanism of Action

Diltiazem produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension; thus hypertensive individuals experience an antihypertensiveeffect, whereas there is only a modest fall in blood pressure in normotensives.

Pharmacodynamics and Clinical Studies

In a randomized, double-blind, parallel-group, dose-response study involving 478 patients with essential hypertension, evening doses of Cardizem LA 120, 240, 360, and 540 mg were compared to placebo and to 360 mg administered in the morning. The mean reductions in diastolic blood pressure by ABPM atroughly 24 hours after the morning (4 AM-8AM) or evening (6 PM-10 PM) administration (i.e., the time corresponding to expected trough serum concentrations) are shown in TABLE 1.

TABLE 1 Mean Change in Trough Diastolic Pressure by ABPM Evening Dosing   120 mg -2.0   240 mg -4.4   360 mg -4.4   540 mg -8.1 Morning Dosing   360 mg -6.4

A second randomized, double-blind, parallel-group, dose-response study (n=258) evaluated Cardizem LA following morning doses of placebo or 120, 180, 300, or 540 mg. Diastolic blood pressure measured by supine office cuff sphygmomanometer at trough (7 AM to 9 AM) decreased in an apparently linear mannerover the dosage range studied. Group mean changes for placebo, 120 mg, 180 mg, 300 mg and 540 mg were -2.6, -1.9, -5.4, -6.1 and -8.6 mm Hg respectively.

Whether the time of administration impacts the clinical benefits of antihypertensive treatment is not known.

Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects.

Like other calcium channel antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.

In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-bloodpressure product for any given work load. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end diastolic pressure have not been affected. Such data has no predictive valuewith respect to effects in patients with poor ventricular function, and increased heart failure has been reported in patients with preexisting impairment of ventricular function. There are as yet few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Restingheart rate is usually slightly reduced by diltiazem. Diltiazem decreases vascular resistance, increases cardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate.

During dynamic exercise, increases in diastolic pressure are inhibited, while maximum achievable systolic pressure is usually reduced. Chronic therapy with diltiazem produces no change or an increase in plasma catecholamines. No increased activity of the renin-angiotensin-aldosterone axis has been observed. Diltiazem reduces the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductions in blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio.

IV diltiazem HCl in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of 300 mg of diltiazem HCl in 6 normal volunteers, the average maximum PR prolongation was 14% with no instances of greaterthan first-degree AV block. Diltiazem associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of diltiazem HCl to patients in doses of up to 540 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation. (See WARNINGS, Cardizem LA Extended Release Tablets).

Pharmacokinetics and Metabolism

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to IV administration) of about 40%. Diltiazem undergoes extensive metabolism in which only 2-4% of the unchanged drug appears in the urine. Drugswhich induce or inhibit hepatic microsomal enzymes may alter diltiazem disposition.

Total radioactivity measurement following short IV administration in healthy volunteers suggests the presence of other unidentified metabolites, which attain higher concentrations than those of diltiazem and are more slowly eliminated; half-life of total radioactivity is about 20 hours compared to 2-5hours for diltiazem.

In vitro binding studies show diltiazem is 70-80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown diltiazem HCl binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide,phenylbutazone, propranolol, salicylic acid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0-4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10-20% of the parent drug and is 25-50% as potent as a coronary vasodilatoras diltiazem. Minimum therapeutic plasma diltiazem concentrations appear to be in the range of 50-200 ng/ml. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose. A study that compared patients with normal hepatic function to patients with cirrhosisfound an increase in half-life and a 69% increase in bioavailability in the hepatically impaired patients. A single study in patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function.

Cardizem LA Tablets

A single 360 mg dose of Cardizem LA results in detectable plasma levels within 3-4 hours and peak plasma levels between 11 and 18 hours; absorption occurs throughout the dosing interval. The apparent elimination half-life for Cardizem LA tablets after single or multiple dosing is 6-9 hours. When CardizemLA tablets were coadministered with a high fat content breakfast, diltiazem peak and systemic exposures were not affected indicating that the tablet can be administered without regard to food.

As the dose of Cardizem LA tablets is increased from 120-240 mg, area-under-the-curve increases 2.5-fold.

Cardizem SR Sustained Release Capsules

The therapeutic effects of Cardizem are believed to be related to its ability to inhibit the influx of calcium ions during membrane depolarization of cardiac and vascular smooth muscle.

Mechanism of Action

Cardizem SR produces its antihypertensive effect primarily by relaxation of vascular smooth muscle and the resultant decrease in peripheral vascular resistance. The magnitude of blood pressure reduction is related to the degree of hypertension; thus hypertensive individuals experience an antihypertensiveeffect, whereas there is only a modest fall in blood pressure in normotensives.

Hemodynamic and Electrophysiologic Effects

Like other calcium antagonists, diltiazem decreases sinoatrial and atrioventricular conduction in isolated tissues and has a negative inotropic effect in isolated preparations. In the intact animal, prolongation of the AH interval can be seen at higher doses.

In man, diltiazem prevents spontaneous and ergonovine-provoked coronary artery spasm. It causes a decrease in peripheral vascular resistance and a modest fall in blood pressure in normotensive individuals and, in exercise tolerance studies in patients with ischemic heart disease, reduces the heart rate-bloodpressure product for any given work load. Studies to date, primarily in patients with good ventricular function, have not revealed evidence of a negative inotropic effect; cardiac output, ejection fraction, and left ventricular end diastolic pressure have not been affected. Increased heart failure has, however,been reported in occasional patients with preexisting impairment of ventricular function. There are as yet few data on the interaction of diltiazem and beta-blockers in patients with poor ventricular function. Resting heart rate is usually unchanged or slightly reduced by diltiazem.

Cardizem SR produces antihypertensive effects both in the supine and standing positions. Postural hypotension is infrequently noted upon suddenly assuming an upright position. No reflex tachycardia is associated with the chronic antihypertensive effects. Cardizem SR decreases vascular resistance, increasescardiac output (by increasing stroke volume), and produces a slight decrease or no change in heart rate. During dynamic exercise, increases in diastolic pressure are inhibited while maximum achievable systolic pressure is usually reduced. Heart rate at maximum exercise does not change or is slightly reduced. Chronic therapy with Cardizem produces no change or an increase in plasma catecholamines. No increased activity of the rennin-angiotensin-aldosterone axis has been observed. Cardizem SR antagonizes the renal and peripheral effects of angiotensin II. Hypertensive animal models respond to diltiazem with reductionsin blood pressure and increased urinary output and natriuresis without a change in urinary sodium/potassium ratio.

IV diltiazem in doses of 20 mg prolongs AH conduction time and AV node functional and effective refractory periods by approximately 20%. In a study involving single oral doses of 300 mg of Cardizem in 6 normal volunteers, the average maximum PR prolongation was 14% with no instances of greater thanfirst-degree AV block. Diltiazem-associated prolongation of the AH interval is not more pronounced in patients with first-degree heart block. In patients with sick sinus syndrome, diltiazem significantly prolongs sinus cycle length (up to 50% in some cases).

Chronic oral administration of Cardizem in doses of up to 360 mg/day has resulted in small increases in PR interval, and on occasion produces abnormal prolongation. (See WARNINGS, Cardizem SR Sustained Release Capsules.)

Pharmacokinetics and Metabolism

Diltiazem is well absorbed from the gastrointestinal tract and is subject to an extensive first-pass effect, giving an absolute bioavailability (compared to IV administration) of about 40%. Cardizem undergoes extensive metabolism in which 2-4% of the unchanged drug appears in the urine. In vitro binding studies show Cardizem is 70-80% bound to plasma proteins. Competitive in vitro ligand binding studies have also shown Cardizem binding is not altered by therapeutic concentrations of digoxin, hydrochlorothiazide, phenylbutazone, propranolol, salicylicacid, or warfarin. The plasma elimination half-life following single or multiple drug administration is approximately 3.0-4.5 hours. Desacetyl diltiazem is also present in the plasma at levels of 10-20% of the parent drug and is 25-50% as potent a coronary vasodilator as diltiazem. Minimum therapeutic plasmalevels of Cardizem appear to be in the range of 50-200 ng/ml. There is a departure from linearity when dose strengths are increased; the half-life is slightly increased with dose. A study that compared patients with normal hepatic function to patients with cirrhosis found an increase in half-life and a 69%increase in bioavailability in the hepatically impaired patients. A single study in 9 patients with severely impaired renal function showed no difference in the pharmacokinetic profile of diltiazem compared to patients with normal renal function.

Cardizem SR Capsules

Diltiazem is absorbed from the capsule formulation to about 92% of a reference solution at steady-state. A single 120 mg dose of the capsule results in detectable plasma levels within 2-3 hours and peak plasma levels at 6-11 hours. The apparent elimination half-life after single or multiple dosing is5-7 hours. A departure from linearity similar to that observed with the Cardizem direct compression tablet is observed. As the dose of Cardizem SR is increased from a daily dose of 120 mg (60 mg bid) to 240 mg (120 mg bid) daily, there is an increase in area-under-the curve of 2.6 times. When the dose isincreased from 240-360 mg daily, there is an increase in area-under-the-curve of 1.8 times. The average plasma levels of the capsule dose twice daily at steady-state are equivalent to the tablet dosed 4 times daily when the same total daily dose is administered.

Cardizem CD Capsules

Cardiac Conduction

Cardizem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (13of 3290 patients or 0.40%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2-5 seconds) after a single dose of 60 mg of diltiazem. (See ADVERSE REACTIONS,Cardizem CD Capsules.)

Congestive Heart Failure

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). An acute study of oral diltiazem in patientswith impaired ventricular function (ejection fraction 24% ± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt). Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function. Experience with the use of Cardizem (diltiazem HCl) in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.

Hypotension

Decreases in blood pressure associated with Cardizem therapy may occasionally result in symptomatic hypotension.

Acute Hepatic Injury

Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. In rare instances, significant elevations in enzymessuch as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1-8 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to Cardizem is uncertain in somecases, but probable in some. (See PRECAUTIONS, Cardizem CD Capsules.)

Cardizem Direct Compression Tablets

Cardiac Conduction

Cardizem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (6of 1243 patientsfro 0.48%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2-5 seconds) after a single dose of 60 mg of diltiazem. (See ADVERSE REACTIONS,Cardizem Direct Compression Tablets.)

Congestive Heart Failure

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index or consistent negative effects on contractility (dp/dt). Experience with the use of Cardizem alone orin combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using the drug in such patients.

Hypotension

Decreases in blood pressure associated with Cardizem therapy may occasionally result in symptomatic hypotension.

Acute Hepatic Injury

In rare instances, significant elevations in enzymes such as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions have been reversible upon discontinuation of drug therapy. The relationship to Cardizem is uncertain in some cases,but probable in some. (See PRECAUTIONS, Cardizem Direct Compression Tablets.)

Cardizem LA Extended Release Tablets

Cardiac Conduction

Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second-or third-degree AV block (13of 3290 patients or 0.40%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2-5 seconds) after a single dose of 60 mg of diltiazem (see ADVERSE REACTIONS,Cardizem LA Extended Release Tablets).

Congestive Heart Failure

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index nor consistent negative effects on contractility (dp/dt). An acute study of oral diltiazem in patients with impaired ventricular function (ejection fraction 24% ± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt). Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function. Experience with the use of diltiazem in combination with beta-blockers in patients with impaired ventricular function is limited. Caution should be exercised when using this combination.

Hypotension

Decreases in blood pressure associated with diltiazem therapy may occasionally result in symptomatic hypotension.

Acute Hepatic Injury

Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. In rare instances, significant elevations in enzymessuch as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1-8 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to diltiazem is uncertain in somecases, but probable in some. (See PRECAUTIONS, Cardizem LA Extended Release Tablets.)

Cardizem SR Sustained Release Capsules

Cardiac Conduction

Cardizem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome. This effect may rarely result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block (9of 2111 patients for 0.43%). Concomitant use of diltiazem with beta-blockers or digitalis may result in additive effects on cardiac conduction. A patient with Prinzmetal's angina developed periods of asystole (2-5 seconds) after a single dose of 60 mg of diltiazem. (See ADVERSE REACTIONS,Cardizem SR Sustained Release Capsules.)

Congestive Heart Failure

Although diltiazem has a negative inotropic effect in isolated animal tissue preparations, hemodynamic studies in humans with normal ventricular function have not shown a reduction in cardiac index or consistent negative effects on contractility (dp/dt). An acute study of oral diltiazem in patientswith impaired ventricular function (ejection fraction 24% ± 6%) showed improvement in indices of ventricular function without significant decrease in contractile function (dp/dt). Experience with the use of Cardizem in combination with beta-blockers in patients with impaired ventricular function islimited. Caution should be exercised when using this combination.

Hypotension

Decreases in blood pressure associated with Cardizem therapy may occasionally result in symptomatic hypotension.

Acute Hepatic Injury

Mild elevations of transaminases with and without concomitant elevation in alkaline phosphatase and bilirubin have been observed in clinical studies. Such elevations were usually transient and frequently resolved even with continued diltiazem treatment. In rare instances, significant elevations in enzymessuch as alkaline phosphatase, LDH, SGOT, SGPT, and other phenomena consistent with acute hepatic injury have been noted. These reactions tended to occur early after therapy initiation (1-8 weeks) and have been reversible upon discontinuation of drug therapy. The relationship to Cardizem is uncertain in somecases, but probable in some. (See PRECAUTIONS, Cardizem SR Sustained Release Capsules.)

Cardizem CD Capsules

General

Cardizem (diltiazem HCl) is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients withimpaired renal or hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liverwhich were reversible when the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatological events (see ADVERSE REACTIONS, Cardizem CD Capsules) may be transient and may disappear despite continued use of Cardizem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologicreaction persist, the drug should be discontinued.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A 24 month study in rats at oral dosage levels of up to 100 mg/kg/day and a 21 month study in mice at oral dosage levels of up to 30 mg/kg/day showed no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivoin mammalian cell assays or in vitro in bacteria. No evidence of impaired fertility was observed in a study performed in male and female rats at oral dosages of up to 100 mg/kg/day.

Pregnancy Category C

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 5-10 times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities.In the perinatal/postnatal studies, there was an increased incidence of stillbirths at doses of 20 times the human dose or greater.

There are no well-controlled studies in pregnant women; therefore, use Cardizem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of Cardizem is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Cardizem Direct Compression Tablets

General

Cardizem is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renalor hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversiblewhen the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatological events (see ADVERSE REACTIONS, Cardizem Direct Compression Tablets) may be transient and may disappear despite continued use of Cardizem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported.Should a dermatologic reaction persist, the drug should be discontinued.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A 24 month study in rats and a 21 month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats.

Pregnancy Category C

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 5-10 times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human dose or greater.

There are no well-controlled studies in pregnant women; therefore, use Cardizem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of Cardizem is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Cardizem LA Extended Release Tablets

General

Diltiazem HCl is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renalor hepatic function.

In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver, which were reversible when thedrug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatological events (see ADVERSE REACTIONS, Cardizem LA Extended Release Tablets) may be transient and may disappear despite continued use of diltiazem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported.Should a dermatologic reaction persist, the drug should be discontinued.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A 24 month study in rats at oral dosage levels of up to 100 mg/kg/day, and a 21 month study in mice at oral dosage levels of up to 30 mg/kg/day showed no evidence of carcinogenicity. There was also no mutagenic response in vitro or in vivoin mammalian cell assays or in vitro in bacteria. No evidence of impaired fertility was observed in a study performed in male and female rats at oral dosages of up to 100 mg/kg/day.

Pregnancy Category C

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 4-6 times (depending on species) the upper limit of the optimum dosage range in clinical trials (480 mg qd or 8 mg/kg qd for a 60 kg patient) resulted in embryo and fetal lethality. These studiesrevealed, in one species or another, a propensity to cause abnormalities of the skeleton, heart, retina, and tongue. Also observed were reductions in early individual pup weights and pup survival, prolonged delivery and increased incident of stillbirths.

There are no well-controlled studies in pregnant women; therefore, use diltiazem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of diltiazem is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of diltiazem 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, doseselection 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.

Cardizem SR Sustained Release Capsules

General

Cardizem is extensively metabolized by the liver and excreted by the kidneys and in bile. As with any drug given over prolonged periods, laboratory parameters of renal and hepatic function should be monitored at regular intervals. The drug should be used with caution in patients with impaired renalor hepatic function. In subacute and chronic dog and rat studies designed to produce toxicity, high doses of diltiazem were associated with hepatic damage. In special subacute hepatic studies, oral doses of 125 mg/kg and higher in rats were associated with histological changes in the liver which were reversiblewhen the drug was discontinued. In dogs, doses of 20 mg/kg were also associated with hepatic changes; however, these changes were reversible with continued dosing.

Dermatological events (see ADVERSE REACTIONS, Cardizem SR Sustained Release Tablets) may be transient and may disappear despite continued use of Cardizem. However, skin eruptions progressing to erythema multiforme and/or exfoliative dermatitis have also been infrequently reported. Should a dermatologic reaction persist, the drug should be discontinued.

Carcinogenesis, Mutagenesis, and Impairment of Fertility

A 24 month study in rats and a 21 month study in mice showed no evidence of carcinogenicity. There was also no mutagenic response in in vitro bacterial tests. No intrinsic effect on fertility was observed in rats.

Pregnancy Category C

Reproduction studies have been conducted in mice, rats, and rabbits. Administration of doses ranging from 5-10 times greater (on a mg/kg basis) than the daily recommended therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies, there was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human dose or greater.

There are no well-controlled studies in pregnant women; therefore, use Cardizem in pregnant women only if the potential benefit justifies the potential risk to the fetus.

Nursing Mothers

Diltiazem is excreted in human milk. One report suggests that concentrations in breast milk may approximate serum levels. If use of Cardizem is deemed essential, an alternative method of infant feeding should be instituted.

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Cardizem CD Capsules

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Cardizem concomitantly with other agents known to affect cardiac contractility and/or conduction. (See WARNINGS, Cardizem CD Capsules.) Pharmacologic studiesindicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Cardizem. (See WARNINGS, Cardizem CD Capsules.)

As with all drugs, care should be exercised when treating patients with multiple medications. Cardizem undergoes biotransformation by cytochrome P-450 mixed function oxidase. Coadministration of Cardizem with other agents which follow the same route of biotransformation may result in the competitiveinhibition of metabolism. Especially in patients with renal and/or hepatic impairment, dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.

Beta-Blockers

Controlled and uncontrolled domestic studies suggest that concomitant use of Cardizem and beta-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Administration of Cardizem (diltiazem HCl) concomitantly with propranolol in 5 normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displacedfrom its binding sites by diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted. (See WARNINGS, Cardizem CD Capsules.)

Cimetidine

A study in 6 healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1 week course of cimetidine at 1200 mg/day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediatedby cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.

Digitalis

Administration of Cardizem with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxinlevels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing Cardizem therapy to avoid possible over- or under-digitalization. (See WARNINGS, Cardizem CD Capsules.)

Anesthetics

The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.

Cyclosporine

A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15-48% was necessary to maintain cyclosporine trough concentrationssimilar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued.

The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Carbamazepine

Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40-72% increase), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

Cardizem Direct Compression Tablets

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Cardizem concomitantly with any agents known to affect cardiac contractility and/or conduction. (See WARNINGS, Cardizem Direct Compression Tablets.)

Pharmacologic studies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Cardizem. (See WARNINGS, Cardizem Direct Compression Tablets.)

As with all drugs, care should be exercised when treating patients with multiple medications. Cardizem undergoes biotransformation by cytochrome P-450 mixed function oxidase. Coadministration of Cardizem with other agents which follow the same route of biotransformation may result in the competitiveinhibition of metabolism. Especially in patients with renal and/or hepatic impairment, dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.

Beta-Blockers

Controlled and uncontrolled domestic studies suggest that concomitant use of Cardizem and beta-blockers is usually well tolerated. Available data are not sufficient, however, to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conductionabnormalities.

Administration of Cardizem concomitantly with propranolol in 5 normal volunteers resulted in increased propranolol levels in all subjects; and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its bindingsites by diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted. (See WARNINGS, Cardizem Direct Compression Tablets.)

Cimetidine

A study in 6 healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1 week course of cimetidine at 1200 mg/day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine.An adjustment in the diltiazem dose may be warranted.

Digitalis

Administration of Cardizem with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxinlevels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing Cardizem therapy to avoid possible over- or under-digitalization. (See WARNINGS, Cardizem Direct Compression Tablets.

Anesthetics

The depression of cardiac contractility, conductivity, and automaticity, as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.

Cyclosporine

A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15-48% was necessary to maintain concentrations similar to thoseseen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted or discontinued. The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Carbamazepine

Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40-72% increase), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

Cardizem LA Extended Release Tablets

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving diltiazem concomitantly with other agents known to affect cardiac contractility and/or conduction (See WARNINGS, Cardizem LA Extended Release Tablets). Pharmacologicstudies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with diltiazem (See WARNINGS, Cardizem LA Extended Release Tablets).

As with all drugs, care should be exercised when treating patients with multiple medications. Diltiazem is both a substrate and an inhibitor of the cytochrome P-450 3A4 enzyme system. Other drugs that are specific substrates, inhibitors, or inducers of this enzyme system may have a significant impacton the efficacy and side effect profile of diltiazem. Patients taking other drugs that are substrates of CYP450, especially patients with renal and/or hepatic impairment, may require dosage adjustment when starting or stopping concomitantly administered diltiazem in order to maintain optimum therapeutic bloodlevels.

Beta-Blockers

Controlled and uncontrolled domestic studies suggest that concomitant use of diltiazem and beta-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Administration of diltiazem concomitantly with propranolol in 5 normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its bindingsites by diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted (See WARNINGS, Cardizem LA Extended Release Tablets).

Cimetidine

A study in 6 healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1 week course of cimetidine at 1200 mg/day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine.An adjustment in the diltiazem dose may be warranted.

Digitalis

Administration of diltiazem with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxinlevels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing diltiazem therapy to avoid possible over- or under-digitalization (See WARNINGS, Cardizem LA Extended Release Tablets).

Anesthetics

The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.

Benzodiazepines

Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to 4-fold and the C_max by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increase (1.5- to 2.5-fold) during coadministration with diltiazem. These pharmacokineticeffects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam.

Cyclosporine

A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15-48% was necessary to maintain cyclosporine trough concentrationssimilar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted, or discontinued.

The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.

Carbamazepine

Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40-72% increase), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

Lovastatin

In a 10-subject study, coadministration of diltiazem (120 mg bid diltiazem SR) with lovastatin resulted in a 3-4 times increase in mean lovastatin AUC and C_max versus lovastatin alone; no change in pravastatin AUC and C_max was observed during diltiazem coadministration.Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

Rifampin

Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP 3A4 inducer should be avoided when possible, and alternative therapy considered.

Cardizem SR Sustained Release Capsules

Due to the potential for additive effects, caution and careful titration are warranted in patients receiving Cardizem concomitantly with any agents known to affect cardiac contractility and/or conduction. (See WARNINGS, Cardizem SR Sustained Release Capsules.) Pharmacologicstudies indicate that there may be additive effects in prolonging AV conduction when using beta-blockers or digitalis concomitantly with Cardizem. (See WARNINGS, Cardizem SR Sustained Release Capsules.)

As with all drugs, care should be exercised when treating patients with multiple medications. Cardizem undergoes biotransformation by cytochrome P-450 mixed function oxidase. Coadministration of Cardizem with other agents which follow the same route of biotransformation may result in the competitiveinhibition of metabolism. Especially in patients with renal and/or hepatic impairment, dosages of similarly metabolized drugs, particularly those of low therapeutic ratio may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.

Beta-Blockers

Controlled and uncontrolled domestic studies suggest that concomitant use of Cardizem and beta-blockers is usually well tolerated, but available data are not sufficient to predict the effects of concomitant treatment in patients with left ventricular dysfunction or cardiac conduction abnormalities.

Administration of Cardizem concomitantly with propranolol in 5 normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its bindingsites by diltiazem. If combination therapy is initiated or withdrawn in conjunction with propranolol, an adjustment in the propranolol dose may be warranted. (See WARNINGS, Cardizem SR Sustained Release Capsules.)

Cimetidine

A study in 6 healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1 week course of cimetidine at 1200 mg/day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.

Digitalis

Administration of Cardizem with digoxin in 24 healthy male subjects increased plasma digoxin concentrations approximately 20%. Another investigator found no increase in digoxin levels in 12 patients with coronary artery disease. Since there have been conflicting results regarding the effect of digoxinlevels, it is recommended that digoxin levels be monitored when initiating, adjusting, and discontinuing Cardizem therapy to avoid possible over- or under-digitalization. (See WARNINGS, Cardizem SR Sustained Release Capsules.)

Anesthetics

The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.

Cyclosporine

A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15-48% was necessary to maintain cyclosporine trough concentrationssimilar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted or discontinued. The effect of cyclosporine on diltiazem plasma concentrations has not beenevaluated.

Carbamazepine

Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40-72% increase), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.

Cardizem CD Capsules

Serious adverse reactions have been rare in studies carried out to date, but it should be recognized that patients with impaired ventricular function and cardiac conduction abnormalities have usually been excluded from these studies.

The TABLE 2 presents the most common adverse reactions reported in placebo-controlled angina and hypertension trials in patients receiving Cardizem CD up to 360 mg with rates in placebo patients shown for comparison.

TABLE 2 Cardizem CD Capsule Placebo-Controlled Angina and Hypertension Trials Combined   Cardizem CD Placebo Adverse Reactions (n=607) (n=301) Headache 5.4% 5.0% Dizziness 3.0% 3.0% Bradycardia 3.3% 1.3% AV block first-degree 3.3% 0.0% Edema 2.6% 1.3% ECG abnormality 1.6% 2.3% Asthenia 1.8% 1.7%

In clinical trials of Cardizem CD capsules, Cardizem tablets, and Cardizem SR capsules involving over 3200 patients, the most common events (i.e., greater than 1%) were edema (4.6%), headache (4.6%), dizziness (3.5%), asthenia (2.6%), first-degree AV block (2.4%),bradycardia (1.7%), flushing (1.4%), nausea (1.4%), and rash (1.2%).

In addition, the following events were reported infrequently (less than 1%) in angina or hypertension trials:

Cardiovascular: Angina, arrhythmia, AV block (second- or third-degree), bundle branch block, congestive heart failure, ECG abnormalities, hypotension, palpitations, syncope, tachycardia, ventricular extrasystoles.

Nervous System: Abnormal dreams, amnesia, depression, gait abnormality, hallucinations, insomnia, nervousness, paresthesia, personality change, somnolence, tinnitus, tremor.

Gastrointestinal: Anorexia, constipation, di