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diltiazem 60 mg tablet (generic cardizem)

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Uses

Diltiazem is used in the management of Prinzmetal variant angina, chronic stable angina pectoris, supraventricular tachycardias, and hypertension.

Angina

Calcium-channel blocking agents are considered the drugs of choice for the management of Prinzmetal variant angina. A nondihydropyridine calcium-channel blocker (e.g., diltiazem, verapamil) also has been recommended in patients with unstable angina who have continuing or ongoing ischemia when therapy with β-blocking agents and nitrates is inadequate, not tolerated, or contraindicated and when severe left ventricular dysfunction, pulmonary edema, or other contraindications are not present. In the management of chronic stable angina pectoris, oral diltiazem appears to be as effective as β-adrenergic blocking agents (e.g., propranolol) and/or oral nitrates; however, oral diltiazem generally should be used in chronic stable angina pectoris only when the patient cannot tolerate adequate doses of or is refractory to these drugs. In short-term, controlled clinical studies in patients with chronic stable angina pectoris, oral diltiazem reduced the frequency of attacks, allowed a decrease in sublingual nitroglycerin dosage, and increased the patient's exercise tolerance. Controlled studies also indicate that concurrent use of oral diltiazem and a β-adrenergic blocking agent in patients with chronic stable angina pectoris may reduce the frequency of attacks and increase exercise tolerance; however, additional study is needed to determine the safety and efficacy of concomitant therapy, especially in patients with compromised left ventricular function or cardiac conduction abnormalities. Although concomitant therapy with oral diltiazem, nitroglycerin, and a β-adrenergic blocking agent may be beneficial in some patients, the safety and/or efficacy of such therapy have not been fully determined. (See Drug Interactions.)

Hypertension

Oral diltiazem is used alone or in combination with other classes of antihypertensive agents in the management of hypertension. Only extended-release formulations are recommended for the management of hypertension.

Calcium-channel blocking agents, such as diltiazem, are considered one of several preferred antihypertensive drugs for the initial management of hypertension; other options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and thiazide diuretics. While there may be individual differences with respect to specific outcomes, these antihypertensive drug classes all produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.

Calcium-channel blockers may be particularly useful in the management of hypertension in black patients; these patients tend to have greater blood pressure response to calcium-channel blockers and thiazide diuretics than to other antihypertensive drug classes (e.g., ACE inhibitors, angiotensin II receptor antagonists). Use of a calcium-channel blocker also may be beneficial in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina) and in geriatric patients, including those with isolated systolic hypertension. () In addition, nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) may be beneficial in hypertensive patients with coexisting atrial fibrillation and a rapid ventricular rate.

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT) study, the long-term cardiovascular morbidity and mortality benefit of a long-acting dihydropyridine calcium-channel blocker (amlodipine), a thiazide-like diuretic (chlorthalidone), and an ACE inhibitor (lisinopril) were compared in a broad population of patients with hypertension at risk for coronary heart disease. Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed. Patients receiving the ACE inhibitor experienced higher risks of stroke, combined cardiovascular disease, GI bleeding, and angioedema, while those receiving the calcium-channel blocker were at higher risk of developing heart failure. The ALLHAT investigators suggested that the favorable cardiovascular outcome may be attributable, at least in part, to the greater antihypertensive effect of the calcium-channel blocker compared with that of the ACE inhibitor, especially in women and black patients.

For additional information on the role of calcium-channel blockers in the management of hypertension, . For information on overall principles and expert recommendations for treatment of hypertension, .

Supraventricular Arrhythmias

Diltiazem is used in the management of supraventricular tachycardias (SVTs), including rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT) (e.g., tachycardia associated with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome), and control of rapid ventricular rate in atrial flutter or fibrillation. The American College of Cardiology/American Heart Association/Heart Rhythm Society (ACC/AHA/HRS) guideline for the management of adults with supraventricular tachycardia recommends the use of diltiazem in the treatment of various SVTs (e.g., atrial flutter, junctional tachycardia, focal atrial tachycardia, atrioventricular nodal reentrant tachycardia [AVNRT]); in general, IV diltiazem is recommended for acute treatment while oral diltiazem is recommended for ongoing management of these arrhythmias. Vagal maneuvers and/or IV adenosine are considered first-line interventions for the acute treatment of patients with SVT and should be attempted prior to other therapies when clinically indicated; if such measures are ineffective or not feasible, a nondihydropyridine calcium-channel blocker (i.e., diltiazem or verapamil) may be considered. Diltiazem should only be used in hemodynamically stable patients who do not have impaired ventricular function.

Paroxysmal Supraventricular Tachycardia

IV diltiazem is used for rapid conversion of PSVT that is uncontrolled or unconverted by vagal maneuvers and adenosine, including atrioventricular nodal reentrant tachycardias and PSVT associated with extranodal accessory pathways (e.g., Wolff-Parkinson-White or Lown-Ganong-Levine syndrome). In about 86-88% of patients with PSVT, IV diltiazem produces rapid conversion (usually within 2-3 minutes of the first or second dose) to sinus rhythm; conversion to sinus rhythm appears to be dose related. Limited data indicate that conversion to sinus rhythm may occur spontaneously in 25% of placebo-treated patients with PSVT. Transient ventricular premature complexes may be present following conversion of PSVT to sinus rhythm but appear to be benign and of little clinical importance. While comparative trials have not been performed with IV diltiazem and other calcium-channel blockers, the efficacy rate of IV diltiazem in converting PSVT to sinus rhythm appears to be similar to that of verapamil.

Oral diltiazem also has been used to prevent PSVT, but efficacy of the drug for this condition has not been established.

Atrial Fibrillation and Flutter

Nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) are recommended as one of several drug therapy options for ventricular rate control in patients with nonpreexcited atrial fibrillation or flutter. Management of atrial fibrillation or flutter depends on the clinical situation and the patient's condition. For acute treatment of atrial fibrillation, IV diltiazem may be used. Cardioversion is indicated, however, in hemodynamically unstable patients. IV diltiazem should not be used when atrial flutter or fibrillation is associated with an accessory pathway that has a short refractory period (e.g., Wolff-Parkinson-White or Lown-Ganong-Levine syndrome) or with preexcited ventricular complexes or wide QRS complexes, since ventricular tachyarrhythmias, including ventricular fibrillation and cardiac arrest, may be precipitated. Although approximately 95% of patients with atrial flutter or fibrillation respond to direct IV injection of 1 or 2 doses with at least a 20% reduction in ventricular rate and this reduction in heart rate is maintained in at least 83% of patients with continuous IV infusion of the drug, IV diltiazem alone rarely (i.e., less than 10% of patients) converts atrial flutter or fibrillation to normal sinus rhythm; limited data indicate that conversion to sinus rhythm may be dose-related and is not usually seen with recommended doses. Conversion to sinus rhythm after drug therapy is more likely to occur in atrial flutter or atrial fibrillation that is of recent onset (i.e., within 24-48 hours) in patients without structural heart disease.

While comparative trials have not been performed with IV diltiazem and IV digoxin, pharmacokinetic data indicate that diltiazem has a faster onset of action than digoxin and may be more useful for slowing ventricular response in patients with atrial flutter or fibrillation. However, because of the potential negative inotropic effect of diltiazem and recent concerns about the use of calcium-channel blockers in acute myocardial infarction (see Cautions: Precautions and Contraindications), these drugs are not recommended as first-line agents following an acute myocardial infarction despite their efficacy in slowing heart rate, especially in patients already receiving a β-adrenergic blocking agent. Generally, calcium-channel blockers (i.e., diltiazem or verapamil) are reserved for the management of atrial fibrillation associated with an acute myocardial infarction when β-blockers are contraindicated or ineffective.(See Uses: Acute Myocardial Infarction.)

Oral diltiazem also has been used to reduce heart rate in patients with atrial fibrillation, but efficacy of the drug for this condition has not been established.

Atrial Tachycardia

IV diltiazem may be used for the acute treatment of patients with hemodynamically stable focal atrial tachycardia (i.e., regular SVT arising from a localized atrial site), and oral diltiazem may be used for ongoing management.

IV diltiazem also may be used in patients with multifocal atrial tachycardia (i.e., rapid, irregular rhythm with at least 3 distinct P-wave morphologies), although such arrhythmia is commonly associated with an underlying condition (e.g., pulmonary, coronary, or valvular heart disease) and is generally not responsive to antiarrhythmic drugs. Antiarrhythmic drug therapy usually is reserved for patients who do not respond to initial attempts at correcting or managing potential precipitating factors (e.g., exacerbation of chronic obstructive pulmonary disease or congestive heart failure, electrolyte and/or ventilatory disturbances, infection, theophylline toxicity) or in whom a precipitating factor cannot be identified. While specific studies have not been performed with IV diltiazem in patients with multifocal atrial tachycardia, the effects of the drug are expected to be similar to that of IV verapamil, which has been shown to have some efficacy in the acute treatment of this arrhythmia. Orally administered diltiazem may be a reasonable choice for chronic suppression of recurrent symptomatic multifocal atrial tachycardia.

Junctional Tachycardia

Diltiazem may be used for the treatment of junctional tachycardia (i.e., nonreentrant SVT originating from the AV junction), a rapid, occasionally irregular, narrow-complex tachycardia. β-Adrenergic blocking agents generally are used for acute termination and/or ongoing management of junctional tachycardia; limited evidence suggests there may be a role for diltiazem when β-blocking agents (particularly propranolol) are ineffective.

Acute Myocardial Infarction

Calcium-channel blocking agents have not proved beneficial in the early treatment or secondary prevention of acute myocardial infarction, and the possibility that they may be harmful has been raised.(See Cautions: Precautions and Contraindications.) However, diltiazem or verapamil generally can be used after an acute myocardial infarction when β-adrenergic blocking agents are ineffective or contraindicated for the relief of ongoing ischemia or to control rapid ventricular response with atrial fibrillation, but only in patients in whom there is no evidence of congestive heart failure, left-ventricular dysfunction, or AV block and only after weighing carefully the potential benefits versus risks, particularly negative inotropic effects and recent concerns about short-acting formulations of the drugs. Diltiazem also may be useful in patients with non-ST-elevation infarction, but only when left-ventricular dysfunction, pulmonary congestion, and congestive heart failure are not present; in such patients, diltiazem can be added to standard therapy after the first 24 hours postinfarction and continued for 1 year if indicated. In patients with first non-Q-wave infarction or first anterior infarction without left-ventricular dysfunction or pulmonary congestion, diltiazem or verapamil may reduce the incidence of reinfarction, but their benefit beyond that of β-adrenergic agents and aspirin is unclear. Evidence from the Multicenter Diltiazem Postinfarction Trial (MDPIT) (Q-wave and non-Q-wave infarction) and the Diltiazem Reinfarction Study (DRS) (non-Q-wave infarction) suggests that patients with non-Q-wave myocardial infarction or those with Q-wave infarction, preserved left-ventricular function, and no clinical evidence of heart failure may benefit from immediate-release diltiazem therapy. However, interpretation of the results of the MDPIT is confounded by the fact that 53 and 55% of placebo- and diltiazem-treated patients, respectively, received β-blockers concomitantly. In addition, at the time these studies were conducted, aspirin therapy for cardiovascular benefit was not as prevalent as it is currently, raising additional uncertainty about the relevance of the findings for contemporary management of acute myocardial infarction. Of particular concern is the detrimental effect of diltiazem on mortality in patients with left-ventricular dysfunction. Therefore, the drug is contraindicated in patients with acute myocardial infarction that is accompanied by left-ventricular dysfunction or congestive heart failure. If β-adrenergic blocking agents are contraindicated or poorly tolerated, diltiazem or verapamil can be considered for secondary prevention as an alternative to β-blockers in patients with preserved left ventricular function.

Other Uses

Diltiazem has been used with good results as an alternative to β-adrenergic blocking agents (e.g., propranolol) for short-term adjunctive therapy in the treatment of tachycardia and tachyarrhythmias in a limited number of patients with hyperthyroidism and/or thyrotoxicosis. Diltiazem hydrochloride (160-480 mg daily in divided doses) has reduced heart rate, blood pressure, and ventricular and supraventricular premature complexes in patients with these conditions. Diltiazem does not affect the underlying disease, which must be treated with antithyroid therapy. While additional study and experience are necessary, diltiazem may be a useful alternative to β-adrenergic blocking agents in patients in whom therapy with these agents is contraindicated or not tolerated.

Dosage and Administration

Administration

Diltiazem hydrochloride is administered by direct IV injection, continuous IV infusion, or orally.

Oral Administration

Diltiazem hydrochloride is administered orally as conventional tablets or as the extended-release capsules (Cardizem CD, Cartia XT) for the treatment of Prinzmetal variant angina and chronic stable angina and as extended-release capsules (Dilacor XR, Tiazac, Diltia XT, Dilt-XR, Taztia XT) or extended-release tablets (Cardizem LA) for the management of chronic stable angina. Diltiazem hydrochloride usually is administered orally as extended-release capsules (Cardizem CD, Cardizem SR, Dilacor XR, Tiazac, Diltia XT, Dilt-XR, Cartia XT, Taztia XT) or as extended-release tablets (Cardizem LA) for the management of hypertension. Diltiazem also has been available as diltiazem malate alone (Tiamate) and in combination with enalapril (Teczem); however, diltiazem malate alone or in combination with enalapril is no longer commercially available in the US.

Directions for administration (e.g., frequency, whether to administer with or without food, potential for opening capsules and mixing with food) may vary by manufacturer and formulation; specific manufacturer's information should be consulted for additional information. Conventional diltiazem hydrochloride tablets are administered orally before meals and at bedtime. The manufacturers of Cardizem CD or Cartia XT extended-release capsules, and Cardizem LA extended-release tablets state that the capsules and extended-release tablets can be given without regard to meals. Cardizem LA extended-release tablets must be swallowed whole and not chewed or crushed. The manufacturers of Dilacor XR, Diltia XT, and Dilt-XR extended-release capsules state that these capsules should be taken on an empty stomach and should be swallowed whole and not opened, chewed, or crushed.

The manufacturers of Tiazac and Taztia XT extended-release capsules state that the entire contents of the capsule may be sprinkled on a small amount of applesauce immediately prior to administration; subdividing the contents of capsules is not recommended. The patient should swallow the entire mixture; chewing should be avoided. Following administration, the patient should drink a glass of cool water to ensure that the beads are swallowed. In addition, the applesauce should not be hot and should be soft enough to be swallowed without chewing. The mixture of applesauce and beads should not be stored for future use.

Parenteral Administration

Diltiazem hydrochloride is administered by direct IV injection or continuous IV infusion in the management of supraventricular tachyarrhythmias.

For direct IV injection or continuous IV infusion, diltiazem is given slowly under continuous ECG and blood pressure monitoring during the administration period. Solutions of the drug should be inspected visually for particulate matter or discoloration prior to IV administration whenever solution and container permit.

IV Injection

When administered by direct IV injection, diltiazem hydrochloride injection containing 5 mg/mL requires no further dilution.

IV Infusion

When administered as a continuous IV infusion, 25, 50, or 50 mL of diltiazem hydrochloride injection containing 5 mg/mL should be added to 100, 250, or 500 mL of a compatible infusion solution (i.e., 0.9% sodium chloride, 5% dextrose, or 5% dextrose and 0.45% sodium chloride) to produce a final diltiazem hydrochloride concentration of 1, 0.83, or 0.45 mg/mL, respectively. Alternatively, IV infusions with a final concentration of 1 mg/mL can be prepared using the single-dose 100-mg ADD-Vantage vials of diltiazem hydrochloride.

Dosage

Potency of diltiazem hydrochloride preparations is expressed in terms of the hydrochloride.(See Chemistry and Stability: Chemistry.)

Dosage of diltiazem hydrochloride must be carefully adjusted according to individual requirements, tolerance, and response. The manufacturers state that dosage of diltiazem for geriatric patients should be selected carefully because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Angina

For the management of Prinzmetal variant angina or chronic stable angina pectoris, the usual initial adult dosage of diltiazem hydrochloride as conventional tablets is 30 mg 4 times daily. Generally, dosage is gradually increased at 1- to 2-day intervals until optimum control of angina is obtained. The average optimum adult dosage range for diltiazem hydrochloride tablets appears to be 180-360 mg daily given in 3 or 4 divided doses. Geriatric patients may respond to lower dosages. After anginal symptoms are controlled, dosage should be gradually reduced to the lowest level that will maintain relief of symptoms.

When diltiazem hydrochloride is administered as extended-release capsules (Tiazac, Dilacor XR, Diltia XT, Dilt-XR, Taztia XT) or as extended-release tablets (Cardizem LA) for the management of chronic stable angina, the usual initial adult dosage is 120 (Dilacor XR, Diltia XT, Dilt-XR), 120-180 (Tiazac, Taztia XT) or 180 mg (Cardizem LA) once daily. When diltiazem hydrochloride is administered as Cardizem CD or Cartia XT extended-release capsules for the management of chronic stable angina and angina secondary to coronary artery spasm, the usual initial adult dosage is 120-180 mg once daily. Dosage should be individualized based on response; when dosage increases are necessary, they should be titrated over 7-14 days. Some patients may respond to higher dosages of up to 360 (Cardizem LA)- 480 mg (Dilacor XR, Diltia XT, Dilt-XR, Cardizem CD, Cartia XT) or, alternatively, up to 540 mg (Tiazac, Taztia XT) once daily.

Hypertension

Usual Dosage

For the management of hypertension in adults receiving diltiazem hydrochloride as monotherapy, the usual initial dosage as the extended-release capsules (Cardizem SR) is 60-120 mg twice daily and as the extended-release capsules (Cardizem CD, Cartia XT, Dilacor XR, Diltia XT, Dilt-XR) or extended-release tablets (Cardizem LA) is 180-240 mg once daily. When the extended-release capsules of diltiazem hydrochloride (Tiazac, Taztia XT) are used, the usual initial dosage is 120-240 mg once daily. Dosage of the drug should be adjusted according to the patient's blood pressure response. Some patients may respond to lower initial dosages; the manufacturers of Dilacor XR, Dilt-XR, and Diltia XT state that patients 60 years of age or older may respond to an initial dosage of 120 mg daily. The maximum hypotensive effect associated with a given dosage level usually is observed within 14 days. Maintenance dosages usually range from 240-360 mg daily, although diltiazem hydrochloride extended-release capsules (Dilacor XR, Diltia XT, Dilt-XR) have been administered during clinical trials in dosages of 180-480 mg once daily, whereas the diltiazem hydrochloride extended-release capsules (Tiazac, Taztia XT, Diltia XT, Dilt-XR) and the extended-release tablets (Cardizem LA) may be administered at dosages of 120-540 mg once daily. If blood pressure is not adequately controlled with diltiazem alone or if adverse effects preclude further upward titration of dosage, another antihypertensive agent can be added; however, dosage of each drug should be adjusted carefully.

The manufacturers of Cardizem CD or Cartia XT extended-release capsules or Cardizem LA extended-release tablets state that patients whose blood pressure is adequately controlled with diltiazem therapy alone or in combination with another antihypertensive agent may be safely switched to Cardizem CD, Cartia XT, or Cardizem LA at the nearest equivalent daily dosage. Subsequent titration of dosage may be necessary depending on the clinical response of the patient. The manufacturers of Cardizem CD or Cartia XT extended-release capsules and Cardizem LA extended-release tablets also state that there is limited clinical experience with diltiazem doses exceeding 360 mg, but doses up to 540 mg have been used during clinical trials; the incidence of adverse effects (especially first-degree AV block, dizziness, sinus bradycardia) increases with increasing dosage. The manufacturers of Dilacor XR, Dilt-XR, and Diltia XT state that although clinical experience is limited, Dilacor XR, Dilt-XR, and Diltia XT extended-release capsules have been administered in 540-mg doses with little or no increased risk of adverse effects.

The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Based on such information, an initial adult dosage of 120-180 mg once daily and target dosage of 360 mg once daily are recommended for extended-release diltiazem hydrochloride. Target dosages of antihypertensive agents generally can be achieved within 2-4 weeks, but it may take up to several months. Antihypertensive therapy should be titrated until goal blood pressure is achieved. If an adequate blood pressure response is not achieved with diltiazem monotherapy, another antihypertensive agent with demonstrated benefit may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents at optimal dosages, a third drug may be added. In patients who experience intolerable adverse effects with diltiazem, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the calcium-channel blocker and initiate another class of antihypertensive agent.

Blood Pressure Monitoring and Treatment Goals

Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of diltiazem hydrochloride is recommended.

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.

Supraventricular Arrhythmias

Paroxysmal Supraventricular Tachycardia

For rapid conversion to normal sinus rhythm in patients with paroxysmal supraventricular tachycardia (PSVT) or for stable, narrow-complex, reentry mechanism tachycardias (reentry SVT), if the rhythm is unresponsive to (i.e., not controlled or converted by) vagal maneuvers or adenosine, the usual initial IV dose of diltiazem hydrochloride is 15-20 mg (0.25 mg/kg) given by direct IV injection over 2 minutes; some patients may respond to an initial dose of 0.15 mg/kg, but duration of action may be shorter and clinical experience with this dose is limited. If the patient tolerates the dose but response is inadequate (i.e., conversion to normal sinus rhythm does not occur) and no hypotension is observed, a second dose of 20-25 mg (0.35 mg/kg) may be given 15 minutes after the initial dose. Some clinicians suggest that additional doses of diltiazem should be given at intervals of no less than 15 minutes to allow for the full effect of the drug on AV conduction to be observed. Greater than recommended dosages (e.g., 0.45 mg/kg) do not appear to be more effective in terminating PSVT. Subsequent direct IV doses should be individualized for each patient. Patients with low body weights should be dosed on a mg/kg basis. The usual adult IV maintenance infusion dose of diltiazem hydrochloride is 5-15 mg/hour.

Atrial Fibrillation and Flutter

For temporary control of rapid ventricular rates in adults with atrial flutter or atrial fibrillation, an IV diltiazem hydrochloride loading dose of 15-20 mg (0.25 mg/kg) is administered by direct injection over 2 minutes; some patients may respond to an initial dose of 0.15 mg/kg, but clinical experience with this dose is limited. If the patient tolerates but does not respond adequately to the initial dose (i.e., does not experience the desired reduction in ventricular rate), a second dose of 20-25 mg (0.35 mg/kg) over 2 minutes may be given 15 minutes after the initial dose. Some clinicians suggest that additional doses of diltiazem should be given at intervals of not less than 15 minutes to allow for the full effect of the drug on AV conduction to be observed. For continued reduction of ventricular rate in patients with atrial flutter or fibrillation who have responded to initial therapy with diltiazem, the rate and duration of the diltiazem maintenance infusion should be adjusted carefully according to the patient's tolerance (e.g., reduction in blood pressure) and response (i.e., reduction in heart rate); infusions may be maintained for up to 24 hours. An initial maintenance infusion at the rate of 10 mg/hour (range: 5-15 mg/hour) is recommended. The maintenance infusion rate may be increased in increments of 5 mg/hour up to, but not exceeding, 15 mg/hour, as needed, if further reduction in heart rate is required. Optimal response usually is achieved with diltiazem hydrochloride maintenance dosages of 10-15 mg/hour, but some patients (e.g., those with small body frame) may achieve adequate heart rate control with infusion rates as low as 5 mg/hour; maintenance dosage requirements may be lower in patients with liver disease or in geriatric patients. The safety and efficacy of maintenance infusion rates exceeding 15 mg/hour for longer than 24 hours have not been established, and use of such dosages is not recommended by the manufacturers.

Once adequate control of heart rate or conversion to normal sinus rhythm has been achieved with diltiazem therapy, therapy with antiarrhythmic agents may be necessary to maintain reduced heart rate in patients with atrial fibrillation or atrial flutter or to prevent the further occurrence of paroxysmal supraventricular tachycardia. Attempts to transfer the patient to alternative antiarrhythmic therapy (e.g., IV or oral digoxin, quinidine, procainamide, oral calcium-channel blockers, oral β-adrenergic blockers) should be made. In controlled clinical trials, transference of therapy occurred within 3-24 hours of administration of direct IV injection of diltiazem. Clinical experience with transferring therapy following maintenance infusion of diltiazem hydrochloride is limited. In determining the appropriateness of transferring therapy, characteristics and dosing guidelines for the alternative drug must be considered.

After an acute reduction of heart rate in patients with atrial fibrillation or flutter is obtained with diltiazem therapy, clinicians may consider cardioversion, anticoagulant therapy (e.g., warfarin) to decrease the risk of peripheral embolization, or oral long-term antiarrhythmic agents, depending on the duration of atrial fibrillation and presence of concurrent cardiac disease.

Other Supraventricular Arrhythmias

For the treatment of other supraventricular tachycardias (e.g., junctional tachycardia, atrial tachycardia) in adults, an initial diltiazem hydrochloride dose of 0.25 mg/kg has been administered by direct IV injection over 2 minutes, followed by a maintenance IV infusion of 5-10 mg/hour (up to 15 mg/hour).

Dosage in Renal and Hepatic Impairment

Diltiazem is metabolized extensively by the liver and excreted in urine and bile. Although specific dosage recommendations for patients with impaired renal function are not available, dosage of diltiazem hydrochloride should be titrated cautiously in these patients. However, some evidence suggests that the pharmacokinetics and bioavailability of the oral drug and its major active metabolite deacetyldiltiazem may not be altered substantially in patients with renal failure.

Diltiazem should be used with caution in patients with hepatic impairment, since acute hepatic injury has been reported rarely.(See Cautions: Hepatic Effects.) In addition, systemic clearance and half-life of the drug are increased in patients with liver cirrhosis receiving oral diltiazem; however, the manufacturers make no specific recommendations for dosage adjustment in patients with impaired hepatic function.

Cautions

In therapeutic dosage, diltiazem usually is well tolerated. Serious adverse reactions requiring discontinuance of diltiazem therapy or dosage adjustment are rare; however, GI tract disturbances, skin eruptions, and bradycardia may result in discontinuance of the drug in about 1% of patients.

Cardiovascular Effects

The most common adverse cardiovascular effect noted with IV diltiazem is symptomatic or asymptomatic hypotension, which occurred in 3.2 or 4.3%, respectively, of patients receiving the drug in clinical trials. Hypotension or postural hypotension also was noted in approximately 1% or less of patients receiving oral diltiazem. If symptomatic hypotension occurs, appropriate therapy (e.g., placement of the patients in the Trendelenburg's position, plasma volume expansion) should be initiated. Hypotension occurred secondary to the vasodilating action of diltiazem on vascular smooth muscle. Vasodilation or flushing occurred in 1.7% of patients receiving IV diltiazem and in approximately 1% or less of patients receiving oral diltiazem in clinical trials.

Adverse cardiovascular effects of diltiazem generally occurring in approximately 1% or less of patients include angina; arrhythmia (e.g., junctional rhythm or isorhythmic dissociation); bradycardia; atrial fibrillation or flutter; chest pain; heart murmur; tachycardia; pallor; phlebitis; asymptomatic asystole; bigeminal extrasystole, ventricular extrasystole; sinus pause; sinus node dysfunction; congestive heart failure; worsening of congestive heart failure (in patients with impaired ventricular function); first-, second-, or third-degree AV block; bundle-branch block; ECG abnormalities; ST elevation; ventricular premature complexes; ventricular tachycardia; ventricular fibrillation; syncope; and palpitation. Some of these effects (e.g., first-degree AV block, bradycardia, ECG abnormalities, flushing) have been reported more frequently (but less than 10%) in patients receiving the drug in placebo-controlled studies for the treatment of angina or hypertension. Swelling and/or edema have been reported in about 2.5-9% or less than 1% of patients receiving the drug orally or IV, respectively. Myocardial infarction or ischemia also has been reported rarely in patients receiving diltiazem; however, this adverse effect is not readily distinguishable from the natural history of the disease in these patients.

GI Effects

Nausea occurs in up to 3% of patients receiving diltiazem. Anorexia, vomiting, diarrhea, abdominal pain, paralytic ileus, dyspepsia, dysgeusia, tooth disorder, eructation, colitis, flatulence, GI hemorrhage, gastric ulcers, thirst, and weight gain have occurred in less than 2% of patients receiving the drug. Constipation or dry mouth has been reported in less than 2% of patients receiving the drug orally and in less than 1% of patients receiving the drug IV.

Nervous System Effects

Adverse nervous system effects of diltiazem generally occurring in about 1-5% of patients include headache, somnolence, insomnia, and abnormal dreams. Dizziness or asthenia occurs in 1-5% of patients receiving the drug orally and in less than 1% of patients receiving the drug IV. However, headache, dizziness, and asthenia reportedly occurred in 8-12, 6-7, and 3-5%, respectively, of patients receiving the drug for hypertension. Other adverse nervous system effects including amnesia, depression, gait abnormality, neuropathy, sweating,paresthesia, personality change, malaise, fever, tinnitus, tremor, vertigo, hypertonia, nervousness, abnormal thinking, and hallucinationshave been reported in less than 1% of patients receiving the drug. Extrapyramidal reactions have been reported rarely in patients receiving diltiazem.

Hepatic Effects

Mild to marked elevations in liver function test results (e.g., serum AST [SGOT], ALT [SGPT], LDH, creatine kinase [CK, creatine phosphokinase, CPK], alkaline phosphatase, bilirubin) and hepatocellular injury have been reported rarely in patients receiving oral diltiazem, usually early in therapy (e.g., 1-8 weeks after initiation); although a causal relationship to the drug is uncertain in most cases, it is likely in some cases. Mild elevations usually were transient and frequently resolved despite continued oral diltiazem therapy. Elevations in some indices of liver function (i.e., AST [SGOT], alkaline phosphatase) also have been reported in less than 1% of patients receiving IV diltiazem. Adverse hepatic effects of oral diltiazem have been reversible following discontinuance of the drug.

High dosages of diltiazem hydrochloride have been associated with hepatic damage in dogs and rats during subacute and chronic toxicity studies. Histologic liver changes occurred in rats receiving oral doses of 125 mg/kg or greater, but the changes were reversible following discontinuance of the drug. Doses of 20 mg/kg have also been associated with hepatic effects in dogs; however, the effects were reversible despite continued administration of the drug.

Local and Dermatologic Effects and Sensitivity Reactions

Pruritus or burning at the injection site was reported in 3.9% of patients receiving IV diltiazem in clinical trials.

Rash has been reported in about 1% of patients receiving diltiazem. A generalized rash characterized by leukocytoclastic vasculitis also has been reported, but a causal relationship to the drug has not been established. Photosensitivity reactions, petechiae, urticaria, contact dermatitis, and skin hypertrophy (nevus) have occurred in less than 1% of patients receiving the drug orally; other allergic reactions also have been reported. Pruritus has been reported in less than 1% of patients receiving the drug orally or IV in clinical trials. Diaphoresis was reported in less than 1% of patients receiving IV diltiazem in clinical trials. Alopecia has occurred infrequently, but a causal relationship to the drug has not been established. Adverse dermatologic effects (e.g., rash) associated with diltiazem may be transient and resolve despite continued therapy with the drug; however, skin eruptions infrequently have progressed to erythema multiforme, toxic epidermal neurolysis, Stevens-Johnson syndrome, and/or exfoliative dermatitis. Recurrence of exfoliative dermatitis with rechallenge also has been reported.(See Cautions: Precautions and Contraindications.) Angioedema (including facial or periorbital edema) has been reported infrequently in patients receiving diltiazem. In at least one patient, a diffuse pruritic erythematous rash was associated with generalized lymphadenopathy and appeared to be a hypersensitivity reaction, which resolved following discontinuance of the drug.

Other Adverse Effects

Hyperuricemia was reported in less than 1% of patients receiving IV diltiazem in clinical trials. Other adverse effects of diltiazem include amblyopia, dyspnea, respiratory distress, epistaxis, rhinitis, pharyngitis, pharyngeal edema,sinusitis or sinus disorder, bronchitis, ocular irritation, ophthalmitis, ocular hemorrhage, otic pain, otitis media, hyperglycemia, nasal congestion, sinus congestion, cough increase, flu syndrome, infection, pain, ecchymosis, osteoarticular pain, respiratory disorder, nocturia, polyuria, albuminuria, crystalluria, cystitis, kidney stones, renal failure, pyelonephritis, urinary tract infection, dysmenorrhea, vaginitis, prostate disease, gout, bone pain, neck pain, neck rigidity, blurred vision, muscle cramps, myalgia, back pain, arthrosis, arthralgia, bursitis, fatigue, accidental injury, gynecomastia, and sexual difficulties (e.g., impotence). Gingival hyperplasia, leukopenia, hemolytic anemia, increased bleeding time, purpura, myopathy, retinopathy, thrombocytopenia, and lymphadenopathy also have been reported rarely; however, a definite causal relationship to the drug has not been established.

Precautions and Contraindications

Some findings concerning possible risks of calcium-channel blocking agents raised concerns about the safety and efficacy of these agents (mainly conventional [short-acting] preparations of nifedipine). Findings of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), which compared long-term therapy with a dihydropyridine-derivative calcium-channel blocker, a thiazide-like diuretic, or an angiotensin-converting enzyme (ACE) inhibitor, however, have failed to support these findings.

Diltiazem shares the toxic potentials of other nondihydropyridine calcium-channel blocking agents, and the usual precautions of these agents should be observed.

IV diltiazem initially should be used only in a setting where ECG and hemodynamic monitoring can be performed and where resuscitative therapy and equipment (e.g., direct-current cardioconverter) are readily available. Once a clinician becomes familiar with an individual patient's response to diltiazem, IV administration of the drug in an office setting may be acceptable. All patients receiving IV diltiazem should be monitored electocardiographically. Because diltiazem decreases peripheral vascular resistance and occasionally causes symptomatic hypotension, blood pressure should be monitored carefully, especially during initiation of therapy or upward adjustment of dosage. In addition, the frequency, duration, and severity of angina may rarely increase during initiation of therapy or upward adjustment of dosage.

Diltiazem should be used with caution in patients with congestive heart failure, especially in those receiving concomitant β-adrenergic blocking agents or digoxin, since diltiazem may precipitate or worsen heart failure in these patients secondary to possible negative inotropic effects. Although negative inotropic effects have been noted in vitro with diltiazem, hemodynamic studies in humans with normal ventricular function and in patients with a compromised myocardium, (e.g., severe congestive heart failure, acute myocardial infarction, hypertrophic cardiomyopathy) have not shown a reduction in cardiac index nor consistent negative effects on contractility. While IV diltiazem has been used successfully in patients with atrial flutter or fibrillation and concurrent moderate to severe congestive heart failure, clinical experience with IV diltiazem in patients with impaired ventricular function is limited, and the manufacturers state that the drug should be used with caution in such patients. Peripheral edema occurring during the course of diltiazem therapy should always be investigated as it may indicate deterioration in left ventricular function induced by the drug.

The manufacturers warn that diltiazem rarely may cause second- or third-degree AV block. If high-degree AV block occurs in patients with sinus rhythm, IV diltiazem should be discontinued and appropriate supportive measures instituted. Diltiazem has been administered IV to patients receiving chronic oral β-adrenergic blocking therapy and the combination generally is well tolerated. However, the possibility of detrimental effects on myocardial contractility, heart rate, or AV conduction with such concomitant therapy should be considered.(See Drug Interactions: β-Adrenergic Blocking Agents.)

The possibility that diltiazem-induced skin eruptions may progress to severe dermatologic reactions (e.g., erythema multiforme, exfoliative dermatitis) should be considered. While these dermatologic effects have not yet been reported with IV diltiazem, they potentially could occur with such administration. If an adverse dermatologic effect persists during diltiazem therapy, the drug should be discontinued.

The manufacturers of diltiazem hydrochloride extended-release capsules (Dilacor XR and Dilt-XR) state that although the drug is contained in a slowly disintegrating matrix instead of nondeformable material, such capsules should be used with caution in patients with preexisting GI narrowing. While obstructive symptoms have not been reported in patients receiving diltiazem extended-release preparations, there have been reports of obstructive symptoms in patients with known GI strictures who were receiving other preparations containing nondeformable materials.

Diltiazem is contraindicated in patients with known hypersensitivity to the drug, sick sinus syndrome (unless a functioning ventricular pacemaker is in place), second- or third-degree AV block (unless a functioning ventricular pacemaker is in place), or severe hypotension (systolic blood pressure less than 90 mm Hg) or cardiogenic shock. Oral diltiazem is contraindicated in patients with acute myocardial infarction with radiographically documented pulmonary congestion. Diltiazem should not be administered IV concomitantly with or within a few hours of IV β-adrenergic blocking agents. Prompt cardioversion to normal sinus rhythm is usually necessary in those patients with supraventricular tachycardias and hemodynamic compromise. Diltiazem also should not be used in patients with ventricular tachycardia, since administration of the drug in patients with wide-complex ventricular tachycardia (i.e., QRS of 0.12 seconds or longer) can result in marked hemodynamic deterioration and ventricular fibrillation; proper diagnosis and differentiation from wide-complex supraventricular tachycardia is imperative when administration of diltiazem is considered. The drug should not be used for the management of atrial flutter or fibrillation in patients with an accessory pathway (e.g., those with Wolff-Parkinson-White or Lown-Ganong-Levine syndrome) since life-threatening adverse effects (e.g., ventricular fibrillation, cardiac arrest) may be precipitated secondary to accelerated AV conduction across aberrant pathways that bypass the AV node.

Pediatric Precautions

Safety and efficacy of diltiazem in children have not been established.

Geriatric Precautions

Diltiazem should be used with caution in geriatric patients, since the plasma half-life of the drug may be prolonged in these patients. Since diltiazem is extensively metabolized in the liver and is excreted by the kidneys, renal and hepatic function should be monitored periodically and the drug should be used cautiously in patients with renal or hepatic impairment. Pending further accumulation of data regarding the long-term safety of diltiazem, the manufacturers recommend that laboratory determinations be made at regular intervals when the drug is used for prolonged periods. While clinical experience to date has not revealed age-related differences in response to diltiazem, clinical studies evaluating diltiazem have not included sufficient numbers of adults 65 years of age or older to determine whether geriatric patients respond differently than younger adults. The manufacturers of diltiazem state that dosage for geriatric patients should be selected carefully because these individuals frequently have decreased hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.

Mutagenicity and Carcinogenicity

In vitro bacterial studies using diltiazem have not shown evidence of mutagenicity. No evidence of carcinogenicity was observed in rats or mice receiving diltiazem dosages up to 100 or 30 mg/kg daily for 24 or 21 months, respectively.

Pregnancy, Fertility, and Lactation

Pregnancy

Diltiazem has produced embryocidal and fetocidal effects, skeletal abnormalities, and reductions in early individual pup weights and survival rates during reproduction studies in mice, rats, and rabbits when given in dosages 5-10 times the usual human daily dosage, and an increased incidence of stillbirths at dosages 20 times or more the usual human dosage. There are no adequate and controlled studies to date with diltiazem in pregnant women, and the drug should be used during pregnancy only when the potential benefits justify the possible risks to the fetus.

Fertility

Reproduction studies in male and female rats using diltiazem dosages of up to 100 mg/kg daily have not revealed evidence of impaired fertility.

Lactation

Because diltiazem is distributed into milk, the manufacturers state that women receiving the drug should not breastfeed their infants; an alternative method of infant feeding should be used if diltiazem therapy is considered necessary in nursing women.

Drug Interactions

In all drug interactions described in the Drug Interactions section, diltiazem hydrochloride was used.

Because of the potential for additive cardiovascular effects, the manufacturers recommend caution when diltiazem is administered concomitantly with other drugs that may decrease peripheral resistance or myocardial filling, contractility, or impulse conduction.

Cardiac Glycosides

There are conflicting reports on whether diltiazem substantially affects the pharmacokinetics of digoxin when the drugs are administered concomitantly. In some studies, diltiazem reportedly increased average steady-state serum digoxin concentrations by about 20-50%, possibly by decreasing the renal and nonrenal clearance of the glycoside; however, in other studies, diltiazem did not substantially alter serum digoxin concentrations. Despite conflicting reports, serum digoxin concentrations should be carefully monitored and the patient observed closely for signs of digoxin toxicity when diltiazem and digoxin are administered concomitantly, especially in geriatric patients, patients with unstable renal function, or those with serum digoxin concentrations in the upper therapeutic range before diltiazem is administered; digoxin dosage should be reduced if necessary. Digoxin does not appear to affect the pharmacokinetics of diltiazem. Concomitant use of diltiazem and a cardiac glycoside may result in an additive effect on AV nodal conduction. Although concomitant therapy with the drugs generally has been well tolerated, patients should be monitored for excessive slowing of the heart rate and/or AV block.

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of diltiazem is mediated principally by the cytochrome P-450 (CYP) isoenzyme 3A4. The possibility exists that drugs that induce, inhibit, or compete for this isoenzyme may alter metabolism of diltiazem and therefore, may alter the efficacy and adverse effect profile of diltiazem.

Diltiazem may competitively inhibit CYP3A4-dependent metabolism of other drugs, potentially altering oral bioavailability and/or clearance of these drugs. Diltiazem has been shown to inhibit metabolism of aminopyrine in vitro, and the drug has substantially reduced antipyrine clearance via apparent inhibition of oxidative metabolism in healthy adults.

Dosage of drugs metabolized via CYP3A4 may require adjustment when concomitant diltiazem therapy is initiated or discontinued in order to maintain optimum therapeutic concentrations of such drugs, particularly drugs with a low therapeutic index or in patients with renal and/or hepatic impairment.

H2-Receptor Antagonists

Concomitant administration of diltiazem and cimetidine may result in increased plasma diltiazem concentrations. Peak plasma diltiazem concentrations were increased by approximately 58% and area under the plasma concentration-time curve by approximately 50% in several healthy adults who received a single, 60-mg oral dose of diltiazem after 1 week of oral cimetidine therapy (1.2 g daily). Concomitant administration of ranitidine produced some but not substantial alterations in these pharmacokinetic parameters of diltiazem. Cimetidine and ranitidine increased peak plasma deacetyldiltiazem concentrations by about 65 and 60%, respectively. Although the precise mechanism of this interaction is not known, cimetidine-induced inhibition of the cytochrome P-450 system may play a role; other mechanisms for the decreased clearance of diltiazem and its deacetyl metabolite also may be involved. Although the clinical importance of this potential interaction has not been elucidated, the effects of diltiazem should be monitored carefully when cimetidine therapy is initiated or discontinued in patients receiving cimetidine; dosage adjustment of diltiazem may be necessary.

Cyclosporine

Concomitant use of diltiazem and cyclosporine has resulted in increased blood cyclosporine concentrations and consequent cyclosporine-induced nephrotoxicity. Although further study is needed, it has been suggested that diltiazem may interfere with metabolism of cyclosporine via CYP3A4 inhibition. The possibility that diltiazem may increase serum cyclosporine concentrations and thereby increase its nephrotoxic potential should be considered if the drugs are used concomitantly. Concomitant administration of cyclosporine with diltiazem (especially when diltiazem therapy is initiated, adjusted, or discontinued) requires monitoring of the concentration of cyclosporine in biologic fluid with appropriate adjustment of cyclosporine dosage.

Carbamazepine

Concomitant use of oral diltiazem and carbamazepine can result in increased serum or plasma carbamazepine concentrations and subsequent neurologic and sensory manifestations of carbamazepine toxicity (e.g., dizziness, diplopia, nausea, anorexia, ataxia, fatigue, listlessness, lethargy, nystagmus, dysmetria, headache, paresthesia, depression, speech disturbances, visual hallucinations, hyperacusis); carbamazepine concentrations may increase by 40-72%. Limited experience indicates that a similar interaction also may occur when verapamil, but not nifedipine, is administered concomitantly with carbamazepine. Although further study is needed, it has been suggested that diltiazem may inhibit hepatic metabolism of carbamazepine via CYP3A4. Because of the risk of carbamazepine toxicity and the possibility of reduced diltiazem effect, concurrent use of diltiazem and carbamazepine should be avoided, if possible. If the combination is used, patients should be monitored closely for manifestations of carbamazepine toxicity and alterations in the pharmacokinetics of the drug during concomitant therapy, adjusting carbamazepine dosage accordingly.

Benzodiazepines

Concomitant use of diltiazem and certain benzodiazepines (e.g., midazolam, triazolam) may result in increased plasma concentrations and decreased plasma clearance of those benzodiazepines. Although the exact mechanism has not been elucidated, diltiazem appears to inhibit the CYP3A4 isoenzyme responsible for metabolism of midazolam and triazolam. Results of clinical studies indicate that concomitant use of diltiazem with midazolam or triazolam increases area under the plasma concentration-time curve (AUC), peak plasma concentrations, and elimination half-lives of these benzodiazepines by about 300-400, 200, and 150-250%, respectively (compared with placebo). This interaction may result in increased adverse effects (e.g., prolonged sedation, respiratory depression) associated with the benzodiazepines.

Buspirone

Concomitant use of diltiazem with buspirone may result in increased mean AUC and peak plasma concentrations of buspirone. Results of a placebo-controlled clinical study indicate that concomitant use of diltiazem with buspirone increases the AUC and peak plasma concentration of buspirone by about 550 and 410%, respectively. The elimination half-life and time to peak plasma concentration of buspirone were not affected by diltiazem. This interaction may result in enhanced effects and increased adverse reactions associated with buspirone. In patients receiving buspirone concomitantly with diltiazem, dosage adjustment of buspirone may be necessary.

Lovastatin

Concomitant use of diltiazem with lovastatin may result in increased mean AUCs and peak plasma concentrations of lovastatin. This drug interaction was not observed when diltiazem was used concomitantly with pravastatin. Although the exact mechanism has not been elucidated, diltiazem appears to inhibit the CYP3A4 isoenzyme responsible for metabolism (mainly first-pass) of lovastatin. Results of a study in a limited number of individuals indicate that administration of diltiazem dosages of 120 mg twice daily for 2 weeks increases the mean AUC and peak plasma concentration of lovastatin by 257% and 333%, respectively. Patients receiving concomitant lovastatin concomitantly with diltiazem should be monitored for evidence of lovastatin toxicity (e.g., rhabdomyolysis, myositis).

Quinidine

Concomitant use of diltiazem with quinidine may result in increases in mean AUC and elimination half-life quinidine and a decrease in oral clearance of quinidine. Results of clinical studies indicate that concomitant use of diltiazem with quinidine increases the AUC and elimination half-life of quinidine by about 51 and 36%, respectively, and decreases quinidine oral clearance by about 33%. Patients receiving quinidine concomitantly with diltiazem should be monitored for evidence of quinidine toxicity and quinidine dosage should be adjusted as necessary.

Rifampin

Rifampin reduces the bioavailability and increases the clearance of diltiazem after oral administration via induction of CYP3A enzymes responsible for the metabolism of diltiazem. In a clinical study, concomitant use of rifampin with diltiazem lowered the plasma diltiazem concentrations to undetectable levels. Concomitant use of diltiazem with rifampin (or any other known inducer of CYP3A4) should be avoided when possible and alternative therapy should be considered.

Atazanavir

Concomitant use of diltiazem and atazanavir sulfate may result in increased plasma concentrations and AUC of diltiazem and an additive effect on PR interval prolongation. Caution is advised if diltiazem and atazanavir are used concomitantly; a 50% reduction in diltiazem dosage and ECG monitoring also are recommended.

β-Adrenergic Blocking Agents

Concomitant use of diltiazem or other nondihydropyridine calcium-channel blocking agent with β-adrenergic blocking agents can have additive negative effects on myocardial contractility, heart rate, and AV conduction. Although controlled studies indicate that concomitant use of diltiazem and a β-adrenergic blocking agent in patients with chronic stable angina may reduce the frequency of angina attacks and increase exercise tolerance and usually is well tolerated, the risk of excessive bradycardia, cardiac conduction abnormalities (AV block), and congestive heart failure may be increased compared with diltiazem alone. Reflex enhancement in autonomic tone secondary to peripheral hypotensive effects has been noted with diltiazem alone, and concomitant use of β-adrenergic blocking agents may increase the sensitivity of the AV node to the direct depressant effects of diltiazem or other nondihydropyridine calcium-channel blocking agent. Slowing or complete suppression of SA node activity with development of slow ventricular rates (e.g., 30-40 bpm), often misdiagnosed as complete AV block, has been reported in patients receiving the nondihydropyridine calcium-channel blocking agent mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-adrenergic blocker therapy.

Diltiazem has been administered IV to patients maintained on oral β-adrenergic blocker therapy, and the combination generally is well tolerated. However, the possibility of detrimental effects on myocardial contractility, heart rate, or AV conduction with such concomitant therapy should be considered. When IV propranolol is used concomitantly with IV diltiazem in patients with coronary artery disease, heart rate and cardiac output are decreased and the PR interval is prolonged. Because of the depressive effects of the drugs on myocardial contractility and AV conduction, IV diltiazem and IV β-adrenergic blocking agents should not be administered within a few hours of each other.

Oral bioavailability of propranolol has been increased by approximately 50% when diltiazem was administered concomitantly in several healthy individuals. Diltiazem has been shown to increase the mean plasma concentrations, elimination half-lives, AUC, and maximum plasma concentrations of propranolol or metoprolol. However, the mean plasma concentration and the pharmacokinetics of atenolol were not affected by concomitant use with diltiazem. In vitro, propranolol appears to be displaced from its binding sites by diltiazem. Dosage adjustment of propranolol may be necessary when concomitant diltiazem therapy is initiated or discontinued.

Nitrates

The manufacturers of diltiazem state that sublingual nitroglycerin may be administered as required during diltiazem therapy for relief of acute angina pectoris. The manufacturers also state that concomitant prophylactic therapy with short- or long-acting nitrates may be administered safely during diltiazem therapy, but that controlled studies to evaluate concomitant use of the drugs have not been performed.

Other Drugs

Depression of cardiac contractility, conductivity, and automaticity as well as vascular dilation associated with the use of general anesthetics may be potentiated by concomitant use of a calcium-channel blocker, including diltiazem. When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully.

Pharmacokinetics

Unless otherwise specified, in all studies described in the Pharmacokinetics section, diltiazem was administered as the hydrochloride salt. The pharmacokinetics of diltiazem are subject to considerable interindividual variation.

Absorption

Approximately 80% of an oral dose of diltiazem hydrochloride is rapidly absorbed from the GI tract following oral administration of conventional tablets of the drug. Only about 40% of an oral dose reaches systemic circulation as unchanged drug since diltiazem undergoes extensive metabolism on first pass through the liver. Oral bioavailability and average plasma concentrations at steady state reportedly are equivalent following oral administration of diltiazem hydrochloride dosages of 120 mg twice daily as extended-release capsules or 60 mg 4 times daily as conventional tablets; however, peak plasma concentration at steady state is lower and the time to peak concentrations is longer with extended-release capsules. The oral bioavailability of Cardizem CD or Cardizem SR extended-release capsules at steady state is about 95 or 92%, respectively, when compared with that of conventional diltiazem hydrochloride tablets. Oral bioavailability of diltiazem hydrochloride increases disproportionately with increasing doses; as the dosage of extended-release capsules increases from 120 to 240 mg daily (60 to 120 mg twice daily), oral bioavailability of the drug approximately triples, as the dosage of conventional tablets or extended-release capsules increases from 240 to 360 mg daily, the oral bioavailability approximately doubles, and as the dosage of extended-release capsules increases from 120 to 540 mg daily, the oral bioavailability of the drug approximately increases sevenfold. As the dose of diltiazem extended-release tablets (Cardizem LA) increases from 120 to 240 mg, the area under the plasma concentration-time curve (AUC) increases by 250%.

Food does not appear to affect the extent of absorption of the (Cardizem CD, Cartia XT) extended-release diltiazem hydrochloride capsules or the (Cardizem LA) extended-release diltiazem hydrochloride tablets; however, rate of absorption may be increased if the extended-release capsules (Tiazac, Taztia XT) are taken with a high-fat meal. Food may affect extent of absorption of some extended-release diltiazem hydrochloride capsules (Dilacor XR, Diltia XT); AUC was increased by 13 or 19%, respectively, while peak plasma concentrations increased by 37 or 51%, respectively, when Dilacor XR or Diltia XT diltiazem extended-release capsules were administered with a high-fat meal, respectively. In healthy geriatric individuals 65-77 years of age who received oral or IV diltiazem, mean AUC of the drug was increased by approximately 50% relative to that in younger adults; these increases were attributed to slower elimination in the geriatric individuals.

Peak serum concentrations usually are reached within 2-3 or 4-11 hours after oral administration of conventional tablets or extended-release capsules, respectively; peak serum concentrations usually are reached within 10-14 hours after oral administration of Cardizem CD extended-release capsules. Peak serum concentrations usually are reached within 11-18 hours following oral administration of diltiazem extended-release tablets (Cardizem LA). In healthy adults, direct IV injection over 3 minutes of a single 10- or 15-mg dose of diltiazem hydrochloride results in median plasma diltiazem concentrations of 104 or 492 ng/mL, respectively. Following continuous infusion of 10 or 15 mg/hour of diltiazem, peak plasma concentrations average 242 or 470 ng/mL, respectively, in patients with atrial flutter/fibrillation and 170 or 270 ng/mL in healthy adults, respectively. After continuous IV infusion at a rate of 10 mg/hour in healthy adults, steady-state plasma diltiazem concentrations average approximately 160 ng/mL.

Plasma concentrations of 50-200 ng/mL appear to be required for antianginal effect. The manufacturer of diltiazem extended-release capsules (Cardizem CD) states that administration of the capsules once daily provides 24-hour blood pressure control. When diltiazem is administered as a continuous IV infusion, plasma diltiazem concentrations of approximately 80-300 ng/mL are required to lower heart rate by 20-40% in patients with atrial flutter or atrial fibrillation; reductions in heart rate tend to correlate with plasma concentrations in these patients but not in healthy adults. Following administration of 1 or 2 direct IV injections of diltiazem hydrochloride, reductions in heart rate usually occur within 3 minutes; maximal heart rate reduction generally occurs within 2-7 minutes and persists for 1-3 hours. Following direct IV injection of diltiazem hydrochloride over a 2-minute period, hemodynamic effects (e.g., decrease in blood pressure) generally occur by the end of the 2-minute period and reach a maximum within 2-11 minutes. Blood pressure reductions following direct IV injection of diltiazem, if they occur, generally are short-lived but may last 1-3 hours. Plasma diltiazem concentrations required to prolong the AH interval in patients with paroxysmal supraventricular tachycardia (PSVT) vary considerably, ranging from 65-260 ng/mL following initial direct IV injection; conversion to normal sinus rhythm usually occurs within a mean of 0.4-8 minutes. Increases in plasma diltiazem concentrations or dosage roughly correlate with prolongation of AV nodal conduction in healthy individuals and patients with PSVT; individual differences in the extent of protein binding, tissue distribution, and autonomic tone may account for variability in the dose-response relationship. After initiation of a continuous IV infusion of diltiazem, effects on the AV node generally occur within minutes and may persist for 0.5-10 hours postinfusion. No consistent relationship has been established between plasma diltiazem concentrations or dosage and overall blood pressure reduction in healthy adults.

Distribution

Diltiazem has a large volume of distribution because of its lipophilicity and is rapidly and extensively distributed into body tissues. The extensive distribution also may be secondary to the relatively high unbound fraction in plasma. The mean apparent volume of distribution of diltiazem at steady state ranges from 360-391 L in healthy adults receiving an IV infusion of 4.8-13.2 mg/hour for 24 hours. About 70-85% of diltiazem is bound to plasma proteins, but only 30-40% is bound to albumin.

Diltiazem is distributed into milk, apparently in concentrations approximately equal to maternal serum concentrations.

Elimination

Following oral administration in healthy individuals, diltiazem has a plasma half-life of 2-11 hours; however, plasma half-life of unidentified metabolites may be increased to about 20 hours. Half-life may be slightly prolonged after multiple oral dosing. Following a single IV injection of diltiazem in healthy adults, pharmacokinetics are dose proportional over a dosage range of 10.5-21 mg with a half-life of approximately 3.4 hours and a systemic clearance of approximately 65 L/hour. In patients with atrial flutter or fibrillation receiving a single IV injection of diltiazem hydrochloride 2.5-38.5 mg, the systemic clearance averages 36 L/hour. After continuous IV infusion (10 and 15 mg/hour) in healthy adults, the plasma elimination half-life increases to 4.1-5 hours and the systemic clearance decreases to 52-68 or 48 L/hour, respectively; pharmacokinetics are nonlinear after continuous IV infusion. In patients with atrial fibrillation or atrial flutter receiving 10 or 15 mg/hour of diltiazem via continuous IV infusion, the half-life increases to 6.8 or 6.9 hours and the systemic clearance decreases to 42 or 31 L/hour, respectively. Plasma half-life of the drug may be increased in geriatric patients, but is unchanged or only slightly increased in patients with renal impairment. Liver cirrhosis has been shown to reduce diltiazem's apparent oral clearance and to prolong its half-life.

Diltiazem is rapidly and almost completely metabolized in the liver via deacetylation, N-demethylation, and O-demethylation to several active and at least 5 inactive metabolites principally via the cytochrome P-450 (CYP) microsomal enzyme system and mainly by the isoenzyme 3A4 (CYP3A4); the drug and its metabolites also undergo glucuronide and/or sulfate conjugation. Plasma diltiazem concentrations are higher following multiple oral doses of the drug than after single oral doses, indicating saturation of hepatic microsomal enzyme systems. Following single diltiazem doses administered via direct IV injection, plasma concentrations of the principal metabolites, deacetyldiltiazem and N-monodesmethyldiltiazem, are low or undetectable; plasma concentrations of active metabolites are detectable generally within 30 minutes of initiation of continuous IV infusion and peak at 0.25-5 hours after infusion. About 10-35% of diltiazem is metabolized to deacetyldiltiazem, which exhibits 25-50% of the coronary vasodilating activity of diltiazem.

The contribution of deacetyldiltiazem and N-monodesmethyldiltiazem to the observed efficacy of diltiazem is unclear. In one study, the plasma concentrations of the active metabolites were low in patients with atrial flutter or fibrillation receiving diltiazem hydrochloride by a continuous IV infusion; the metabolites are thought to contribute little to clinical response. However, data from a study in healthy individuals indicate the presence of appreciable concentrations of active metabolites following continuous IV infusion of the drug. Other unidentified metabolites were noted in the plasma after short-term IV administration in healthy adults and appeared in higher concentrations than unchanged diltiazem; these metabolites were more slowly eliminated than the parent drug.

Approximately 2-4% of a dose of the drug is excreted in urine unchanged. The remainder of the drug is eliminated in urine and via bile, mainly as metabolites.

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