AHFS Class:

• Class IV Antiarrhythmics 24:04.04.24

Generic Name(s):

• dilTIAZem Hydrochloride

Diltiazem is a nondihydropyridine calcium-channel blocking agent (calcium-channel blocker).

Diltiazem is used in the management of Prinzmetal variant angina, chronic stable angina pectoris, supraventricular tachycardias, and hypertension.237,700,701

Angina

Diltiazem is used in the management of angina, including chronic stable angina, Prinzmetal variant angina, and unstable angina†.1100,1101 Calcium-channel blockers (used alone or in combination with nitrates) are considered the drugs of choice for the management of Prinzmetal variant angina.1100β-Adrenergic blocking agents (β-blockers) are recommended as the anti-ischemic drugs of choice in most patients with chronic stable angina; however, calcium-channel blockers may be substituted or added in patients who do not tolerate or respond adequately to β-blockers.1101 In short-term, controlled clinical studies in patients with chronic stable angina, oral diltiazem reduced the frequency of attacks, allowed a decrease in sublingual nitroglycerin dosage, and increased exercise tolerance. All classes of calcium-channel blockers appear to be equally effective in reducing anginal episodes; however, choice of a specific agent should be individualized since the pharmacologic properties of these drugs differ.1101

Diltiazem also may be beneficial in patients with unstable angina†; experts recommend the use of a nondihydropyridine calcium-channel blocker (e.g., diltiazem, verapamil) for the relief of ongoing or recurrent ischemia when β-blocker therapy is inadequate, not tolerated, or contraindicated in patients with unstable angina who do not have clinically important left ventricular dysfunction, increased risk of cardiogenic shock, or AV block.1100

Although concurrent use of some calcium-channel blockers and a β-blocker may have beneficial effects in some patients (e.g., reduction of dihydropyridine-induced tachycardia through β-blockade), combined use of diltiazem with a β-blocker generally should be avoided because of the potential adverse effects on AV nodal conduction, heart rate, and cardiac contractility.1101 (See β-Adrenergic Blocking Agents under Drug Interactions: Drugs Known to Impair Cardiac Contractility and Conduction.)

Hypertension

Oral diltiazem is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.138,187,188,189,190,272,1200 Only extended-release formulations of diltiazem are recommended for the management of hypertension.1200

Calcium-channel blockers (e.g., diltiazem) are considered one of several preferred antihypertensive drug classes for the initial management of hypertension according to current evidence-based hypertension guidelines; other preferred options include angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists, and thiazide diuretics.501,502,503,504,1200 While there may be individual differences with respect to recommendations for initial drug selection and use in specific patient populations, current evidence indicates that these antihypertensive drug classes all generally produce comparable effects on overall mortality and cardiovascular, cerebrovascular, and renal outcomes.501,502,504,1200,1213 (See Uses: Hypertension, in Amlodipine 24:28.08.)

Calcium-channel blockers may be particularly useful in the management of hypertension in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina)146,148,159,160,169,523 and in geriatric patients, including those with isolated systolic hypertension.147,153,154,166,167,170,171,502,510 (See Uses: Hypertension, in Amlodipine 24:28.08.) In addition, nondihydropyridine calcium-channel blockers may be beneficial in hypertensive patients with coexisting atrial fibrillation and a rapid ventricular rate.502,504 However, some experts recommend against the use of nondihydropyridine calcium-channel blockers in patients who have heart failure with reduced ejection fraction because of the drugs' myocardial depressant activity and unfavorable outcomes in some clinical trials in patients with heart failure receiving the drugs.1200,1250

In the Antihypertensive and Lipid-lowering Treatment to Prevent Heart Attack Trial (ALLHAT), 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.316,317,327,328,329,330 Although these antihypertensive agents were comparably effective in providing important cardiovascular benefit, apparent differences in certain secondary outcomes were observed.316,317 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.329,330 The ALLHAT investigators suggested that the observed differences in 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.329,330 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)

Most patients with hypertension, especially black patients, will require at least 2 antihypertensive drugs to achieve adequate blood pressure control.1200 Calcium-channel blockers may be particularly useful in the management of hypertension in black patients;150,165,166,167,168,169,327,328 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).501,504,1200 However, the combination of an ACE inhibitor or an angiotensin II receptor antagonist with a calcium-channel blocker or thiazide diuretic produces similar blood pressure lowering in black patients as in other racial groups.1200 (See Race under Hypertension: Other Special Considerations for Antihypertensive Therapy, in Uses in Amlodipine 24:28.08.)

For additional information on the role of calcium-channel blockers in the management of hypertension, see Uses: Hypertension, in Amlodipine 24:28.08. For information on overall principles and expert recommendations for treatment of hypertension, see Uses: Hypertension in Adults, and also see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

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.237,238,239,244,245,247,250,252,253,256,257,258,262,700,701 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.700,701 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.700 Diltiazem should only be used in hemodynamically stable patients who do not have impaired ventricular function.700

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).237,250,256,700 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.191,237,238,250,256 Limited data indicate that conversion to sinus rhythm may occur spontaneously in 25% of placebo-treated patients with PSVT.256 Transient ventricular premature complexes may be present following conversion of PSVT to sinus rhythm but appear to be benign and of little clinical importance.237,250 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.191,238,252,257

Oral diltiazem also has been used to prevent PSVT, but efficacy of the drug for this condition has not been established.248,260

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.700,701 Management of atrial fibrillation or flutter depends on the clinical situation and the patient's condition.240,258 For acute treatment of atrial fibrillation, IV diltiazem may be used.701 Cardioversion is indicated, however, in hemodynamically unstable patients.701 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.191,237,240,261,262,701 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.191,237,238,244,245,252 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.245

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.245,258 Calcium-channel blockers (i.e., diltiazem or verapamil) may be used for the management of atrial fibrillation associated with an acute myocardial infarction (MI) in patients with a β-blocker intolerance.527 (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.244,252

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.700

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.700 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.312,700 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.700 Orally administered diltiazem may be a reasonable choice for chronic suppression of recurrent symptomatic multifocal atrial tachycardia.700

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.700β-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.700

Acute Myocardial Infarction

Calcium-channel blockers have been used in the early treatment and secondary prevention of acute MI†; although these drugs are effective anti-ischemic agents, they have not demonstrated mortality benefits and therefore are generally used as an alternative to β-blockers.266,527,1100 A review of 28 randomized controlled studies involving 19,000 patients found no benefit with regard to infarct size, rate of reinfarction, or death when calcium-channel blockers were used during the acute or convalescent phase of ST-segment-elevation MI (STEMI).235,527 Although some studies demonstrated a reduced risk of reinfarction when verapamil or diltiazem was administered after MI in patients without left ventricular dysfunction, other studies have not confirmed this finding.1100 Calcium-channel blockers generally are used for their anti-ischemic and blood pressure-reducing properties in the MI setting, and only when β-blockers (which have been shown to reduce mortality after MI) are ineffective, not tolerated, or contraindicated; because the nondihydropyridine calcium-channel blockers (verapamil and diltiazem) can cause substantial negative inotropic effects, their use should be limited to patients without left ventricular dysfunction.527,702,1100

Current expert guidelines state that a calcium-channel blocker may be used to relieve ischemic symptoms, lower blood pressure, or control rapid ventricular response associated with atrial fibrillation in patients with STEMI who are intolerant to β-blockers.527 A nondihydropyridine calcium-channel blocker (e.g., verapamil or diltiazem) may be used as an alternative to β-blockers for relief of ongoing or recurring ischemia when β-blocker therapy is inadequate, not tolerated, or contraindicated in patients with non-ST-segment-elevation MI (NSTEMI) who do not have clinically important left ventricular dysfunction, increased risk of cardiogenic shock, or AV block.1100 The use of immediate-release nifedipine is generally contraindicated because of the potential for hypotension and reflex sympathetic activation.527,1100

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†.172,173,174 Diltiazem hydrochloride (160-480 mg daily in divided doses) has reduced heart rate,172,173,174 blood pressure,173,174 and ventricular and supraventricular premature complexes in patients with these conditions.172 Diltiazem does not affect the underlying disease,172 which must be treated with antithyroid therapy.175,176,177,178 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.172,173

Administration

Diltiazem hydrochloride is administered by direct IV injection, continuous IV infusion, or orally.138,187,190,237,323

Oral Administration

Diltiazem hydrochloride is administered orally as conventional tablets, extended-release capsules, and extended-release tablets.100,187,274,323,324,325,326,600 Diltiazem also has been available as diltiazem malate alone or in combination with enalapril, but these preparations no longer are commercially available in the US.

Directions for administration (e.g., dosing frequency, whether to administer with or without food, potential for opening capsules and mixing with food) may vary by manufacturer and formulation; the manufacturer's information for a specific preparation should be consulted for detailed information.

IV Administration

Diltiazem hydrochloride is administered by direct IV injection or continuous IV infusion in the management of supraventricular tachyarrhythmias.237,703

For direct IV injection or continuous IV infusion, diltiazem is given slowly under continuous ECG and blood pressure monitoring during the administration period.237 Solutions of the drug should be inspected visually for particulate matter or discoloration prior to IV administration whenever solution and container permit.237

IV injection:When administered by direct IV injection, diltiazem hydrochloride injection containing 5 mg/mL requires no further dilution.237

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.237 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.332

Standardize 4 Safety

Standardized concentrations for IV diltiazem have been established through Standardize 4 Safety (S4S), a national patient safety initiative to reduce medication errors, especially during transitions of care. 333Multidisciplinary expert panels were convened to determine recommended standard concentrations. 333Because recommendations from the S4S panels may differ from the manufacturer's prescribing information, caution is advised when using concentrations that differ from labeling, particularly when using rate information from the label. 333 For additional information on S4S (including updates that may be available), see [Web]. 333

Dosage

Potency of diltiazem hydrochloride preparations is expressed in terms of the hydrochloride.179,236,237 (See Chemistry and Stability: Chemistry.)

Dosage of diltiazem hydrochloride must be carefully adjusted according to individual requirements, tolerance, and response.100,138,187,237 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.100,138,187,274,323,326

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.100 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.100 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^®, Dilt-XR^®, Taztia XT^®)274,324,326 or extended-release tablets (Cardizem^® LA, Matzim^® LA)323 for the management of chronic stable angina, the usual initial adult dosage is 120 mg (Dilt-XR^®), 120-180 mg (Tiazac^®, Taztia XT^®) or 180 mg (Cardizem^® LA, Matzim^® LA) once daily.274,323,324,326,600 When diltiazem hydrochloride is administered as Cardizem^® CD187 or Cartia XT^® extended-release capsules325 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.187,325

Dosage should be individualized based on response; when dosage increases are necessary, they should be titrated over 7-14 days.187,274,323,324,325,326,600 Some patients may respond to higher dosages of up to 360 mg (Cardizem^® LA, Matzim^® LA), 480 mg (Dilt-XR^®, Cardizem CD^®, Cartia XT^®), or 540 mg (Tiazac^®, Taztia XT^®) once daily.187,274,323,324,325,326,600

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^® CD, Cartia XT^®, Dilt-XR^®) or extended-release tablets (Cardizem^® LA, Matzim^® LA) is 180-240 mg once daily.138,187,323,324,325,600 When the extended-release capsules of diltiazem hydrochloride (Tiazac^®, Taztia XT^®) are used, the usual initial dosage is 120-240 mg once daily.274,326 Dosage of the drug should be adjusted according to the patient's blood pressure response.138,190,274 Some patients may respond to lower initial dosages;187,323,324,325,600 the manufacturer of Dilt-XR^® states that patients 60 years of age or older may respond to an initial dosage of 120 mg daily.324 The maximum hypotensive effect associated with a given dosage level usually is observed within 14 days.138,187,274,275,323,325,326,600 Some manufacturers state that maintenance dosages usually range from 240-360 mg daily,138,187,325 although diltiazem hydrochloride extended-release capsules (Dilt-XR^®) have been administered during clinical trials in dosages of 180-480 mg once daily,324 and the diltiazem hydrochloride extended-release capsules (Tiazac^®, Taztia XT^®,Dilt-XR^®) and the extended-release tablets (Cardizem^® LA, Matzim^® LA) may be administered at dosages of 120-540 mg once daily.274,323,324,326,600 Some experts state that the usual maintenance dosage of extended-release diltiazem hydrochloride for the management of hypertension is 120-360 mg once daily.1200

The manufacturers of Cardizem^® CD or Cartia XT^® extended-release capsules or Cardizem^® LA or Matzim^® 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^®, Cardizem^® LA, or Matzim^® LA at the nearest equivalent daily dosage.187,323,325,600 Subsequent titration of dosage may be necessary depending on the clinical response of the patient.187,323,325,600 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.187,323,325 The manufacturer of Dilt-XR^® states that although clinical experience is limited, Dilt-XR^® extended-release capsules have been administered in 540-mg doses with little or no increased risk of adverse effects.324

Blood Pressure Monitoring and Treatment Goals

Blood pressure should be monitored regularly (i.e., monthly) during therapy and dosage of the antihypertensive drug adjusted until blood pressure is controlled.1200 If an adequate blood pressure response is not achieved with diltiazem monotherapy, another antihypertensive agent with demonstrated benefit and preferably with a complementary mechanism of action (e.g., angiotensin-converting enzyme [ACE] inhibitor, angiotensin II receptor antagonist, thiazide diuretic) may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents, a third drug may be added.1200 (See Uses: Hypertension in Adults, in the Thiazides General Statement 40:28.20.) In patients who develop unacceptable adverse effects with diltiazem, the drug should be discontinued and another antihypertensive agent from a different pharmacologic class should be initiated.1216

The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure.1200 However, the optimum blood pressure threshold for initiating antihypertensive drug therapy and specific treatment goals remain controversial.505,506,507,508,515,523,530,1201,1207,1209,1222 While other hypertension guidelines have based target blood pressure goals on age and comorbidities,501,504,536 the 2017 American College of Cardiology (ACC)/ American Heart Association (AHA) hypertension guideline incorporates underlying cardiovascular risk into decision making regarding treatment and generally recommends the same target blood pressure (i.e., less than 130/80 mm Hg) in all adults.1200 Many patients will require at least 2 drugs from different pharmacologic classes to achieve this blood pressure goal; the potential benefits of hypertension management and drug cost, adverse effects, and risks associated with the use of multiple antihypertensive drugs also should be considered when deciding a patient's blood pressure treatment goal.1200,1220

For additional information on target levels of blood pressure and on monitoring therapy in the management of hypertension, see Blood Pressure Monitoring and Treatment Goals under Dosage: Hypertension, in Dosage and Administration in the Thiazides General Statement 40:28.20.

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 0.25 mg/kg based on actual body weight (20 mg is reasonable for the average adult) 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.256,700,703 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 0.35 mg/kg based on actual body weight (25 mg is reasonable for the average adult) may be given 15 minutes after the initial dose.257,703 Subsequent doses should be individualized for each patient.703 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.256 Patients with low body weights should be dosed on a mg/kg basis.703 The usual adult IV maintenance infusion dose of diltiazem hydrochloride is 5-15 mg/hour.700,703

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 0.25 mg/kg based on actual body weight (20 mg is reasonable for the average adult) is administered by direct IV injection over 2 minutes;703 some patients may respond to an initial dose of 0.15 mg/kg, but clinical experience with this dose is limited.703 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 0.35 mg/kg based on actual body weight (25 mg is reasonable for the average adult) may be given 15 minutes after the initial dose.246,703 Subsequent doses should be individualized for each patient.703 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.246 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.270,703 An initial maintenance infusion at the rate of 10 mg/hour (range: 5-15 mg/hour) is recommended.293,703 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.293,703 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.245,703 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.244,293,703

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.237 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.237,252,253 In controlled clinical trials, transference of therapy occurred within 3-24 hours of administration of direct IV injection of diltiazem.237,252 Clinical experience with transferring therapy following maintenance infusion of diltiazem hydrochloride is limited.237,252,253 In determining the appropriateness of transferring therapy, characteristics and dosing guidelines for the alternative drug must be considered.237

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.240,244,245

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).700

Dosage in Renal and Hepatic Impairment

Diltiazem is metabolized extensively by the liver and excreted in urine and bile.135,237 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.135,237

Diltiazem should be used with caution in patients with hepatic impairment, since acute hepatic injury has been reported rarely.237,246 (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.237

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,247,252 which occurred in 3.2 or 4.3%, respectively, of patients receiving the drug in clinical trials.237 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.237 Hypotension occurred secondary to the vasodilating action of diltiazem on vascular smooth muscle.237 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.237,252

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.100,138,187,190,237,274,275,324 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.138,187 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.100,114,138,187,190,237 Myocardial infarction (MI) 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.138,187,237,274,275

GI Effects

Nausea occurs in up to 3% of patients receiving diltiazem.100,114,138,187,237,252,274,275 Anorexia,100,115,138,274 vomiting,100,114,115,237,252,274 diarrhea,100,114,115,138,187,190,274,275 abdominal pain,190 paralytic ileus,198 dyspepsia,100,138,187 dysgeusia,100,138,190,274,324 tooth disorder,190 eructation,190 colitis,190 flatulence,190 GI hemorrhage,190 gastric ulcers,190 thirst,138 and weight gain100,138 have occurred in less than 2% of patients receiving the drug.100,138 Constipation100,114,115,138,237,274,275 or dry mouth190,237,274 has been reported in less than 2% of patients receiving the drug orally100,114,115,138,190,274 and in less than 1% of patients receiving the drug IV.237

Nervous System Effects

Adverse nervous system effects of diltiazem generally occurring in about 1-5% of patients include headache,100,114,115,187 somnolence,100,114,138,187,274 insomnia,100,138,187 and abnormal dreams.190,274 Dizziness100,114,115,138,187,237 or asthenia100,115,138,187,237 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.138 Other adverse nervous system effects including amnesia,100,138 depression,100,138,274 gait abnormality,100,138 neuropathy,190 sweating,190 paresthesia,100,114,138,190,237 personality change,100,138 malaise,190 fever,190 tinnitus,100,138 tremor,100,138 vertigo,190 hypertonia,190 nervousness,100,114,138 abnormal thinking,190 and hallucinations100,114,138 have been reported in less than 1% of patients receiving the drug.100,114,190,274 Extrapyramidal reactions have been reported rarely in patients receiving diltiazem.187

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.100,138,187,274 Mild elevations usually were transient and frequently resolved despite continued oral diltiazem therapy.138 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.237 Adverse hepatic effects of oral diltiazem have been reversible following discontinuance of the drug.100,114,138,274

High dosages of diltiazem hydrochloride have been associated with hepatic damage in dogs and rats during subacute and chronic toxicity studies.100,114,138 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.100,114,138 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.100,114,138

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.237

Rash has been reported in about 1% of patients receiving diltiazem.100,115,138,187,190,274,275 A generalized rash characterized by leukocytoclastic vasculitis also has been reported, but a causal relationship to the drug has not been established.138,187,274 Photosensitivity reactions,100,114,138,274 petechiae,100,114,138,274 urticaria,100,114,138 contact dermatitis,324 and skin hypertrophy (nevus)190 have occurred in less than 1% of patients receiving the drug orally;100,114,138 other allergic reactions also have been reported.323 Pruritus has been reported in less than 1% of patients receiving the drug orally or IV in clinical trials.237 Diaphoresis was reported in less than 1% of patients receiving IV diltiazem in clinical trials.237 Alopecia has occurred infrequently, but a causal relationship to the drug has not been established.100,138,274 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.100,138,187,190,274 Recurrence of exfoliative dermatitis with rechallenge also has been reported.138 (See Cautions: Precautions and Contraindications.) Angioedema (including facial or periorbital edema) has been reported infrequently in patients receiving diltiazem.323 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.119

Other Adverse Effects

Hyperuricemia was reported in less than 1% of patients receiving IV diltiazem in clinical trials.237 Other adverse effects of diltiazem include amblyopia,100,138,237 dyspnea,100,138,190,237,274 respiratory distress,324 epistaxis,100,138,190,274 rhinitis,190,274 pharyngitis,190,274 pharyngeal edema,275 sinusitis190 or sinus disorder,275 bronchitis,190,274 ocular irritation,100,138 ophthalmitis,324 ocular hemorrhage,324 otic pain,324 otitis media,324 hyperglycemia,100,138,274 nasal congestion,100,138,274 sinus congestion,323 cough increase,190,274,275 flu syndrome,190,274 infection,324 pain,324 ecchymosis,323 osteoarticular pain,100,114,138 respiratory disorder,190 nocturia,100,114,138 polyuria,100,114,138 albuminuria,323 crystalluria,323 cystitis,190 kidney stones,190 renal failure,324 pyelonephritis,324 urinary tract infection,324 dysmenorrhea,190 vaginitis,190 prostate disease,190 gout,190 bone pain,190 neck pain,190 neck rigidity,324 blurred vision,190 muscle cramps,323 myalgia,190,274 back pain,190 arthrosis,190 arthralgia,190 bursitis,190 fatigue,323 accidental injury,324 gynecomastia,323 and sexual difficulties (e.g., impotence).100,138 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.100,138,190

Precautions and Contraindications

Some findings concerning possible risks of calcium-channel blockers raised concerns about the safety and efficacy of these agents (mainly conventional [short-acting] preparations of nifedipine).209,210,211,213,214,215,216,217,218,219,220,221,222,223,224,225,226,227,228,229,230,231,232,233,235,254,256 (See Cautions, in Nifedipine 24:28.08.) 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.317,321,327,328 (See Clinical Benefits of Thiazides in Hypertension under Hypertension in Adults: Treatment Benefits, in Uses in the Thiazides General Statement 40:28.20.)

Diltiazem shares the toxic potentials of other nondihydropyridine calcium-channel blockers, 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.237,245 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.237 All patients receiving IV diltiazem should be monitored electocardiographically.245 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.237,251,254,256,258 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 MI, hypertrophic cardiomyopathy) have not shown a reduction in cardiac index nor consistent negative effects on contractility.237,253,254,255 While IV diltiazem has been used successfully in patients with atrial flutter or fibrillation and concurrent moderate to severe congestive heart failure,238,247,251,253,254 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.237 If high-degree AV block occurs in patients with sinus rhythm, IV diltiazem should be discontinued and appropriate supportive measures instituted.237 Diltiazem has been administered IV to patients receiving chronic oral β-adrenergic blocking therapy and the combination generally is well tolerated.237 However, the possibility of detrimental effects on myocardial contractility, heart rate, or AV conduction with such concomitant therapy should be considered.237 (See β-Adrenergic Blocking Agents under Drug Interactions: Drugs Known to Impair Cardiac Contractility and Conduction.)

The possibility that diltiazem-induced skin eruptions may progress to severe dermatologic reactions (e.g., erythema multiforme, exfoliative dermatitis) should be considered.100,138,237 While these dermatologic effects have not yet been reported with IV diltiazem, they potentially could occur with such administration.237 If an adverse dermatologic effect persists during diltiazem therapy, the drug should be discontinued.100,138,237

The manufacturer of diltiazem hydrochloride extended-release capsules (Dilt-XR^®) states 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.324 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.190,277,324

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.237,252,253,256,258 Oral diltiazem is contraindicated in patients with acute MI with radiographically documented pulmonary congestion.138,187,190,200,237 Diltiazem should not be administered IV concomitantly with or within a few hours of IV β-adrenergic blocking agents.237 Prompt cardioversion to normal sinus rhythm is usually necessary in those patients with supraventricular tachycardias and hemodynamic compromise.237,240,245,258,261 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.237,257 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.237,262

Pediatric Precautions

Safety and efficacy of diltiazem in children have not been established. For information on overall principles and expert recommendations for treatment of hypertension in pediatric patients, see Uses: Hypertension in Pediatric Patients, in the Thiazides General Statement 40:28.20.

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.100,138,187,274,323,326 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.100,138,187,274,323,326

Mutagenicity and Carcinogenicity

In vitro bacterial studies using diltiazem have not shown evidence of mutagenicity.100,187 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.100,187,274

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.100 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.100

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.100,187

Lactation

Because diltiazem is distributed into milk,100,101 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.100,187,190

In all drug interactions described in the Drug Interactions section, diltiazem hydrochloride was used.275

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.100,187,190,237

Cardiac Glycosides

There are conflicting reports on whether diltiazem substantially affects the pharmacokinetics of digoxin when the drugs are administered concomitantly.100,102,103,104,105,106,107,108,109,110,111 In some studies, diltiazem reportedly increased average steady-state serum digoxin concentrations by about 20-50%,102,105,107,108 possibly by decreasing the renal and nonrenal clearance of the glycoside;104,105,107,108 however, in other studies, diltiazem did not substantially alter serum digoxin concentrations.103,106,109,110 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.103,105,107,108,111 Digoxin does not appear to affect the pharmacokinetics of diltiazem.103,104,105 Concomitant use of diltiazem and a cardiac glycoside may result in an additive effect on AV nodal conduction.100,237 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.100,237

Drugs Affecting Hepatic Microsomal Enzymes

Metabolism of diltiazem is mediated principally by the cytochrome P-450 (CYP) isoenzyme 3A4.100,138,187,274 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.100,138,187,274

Diltiazem may competitively inhibit CYP3A4-dependent metabolism of other drugs, potentially altering oral bioavailability and/or clearance of these drugs.100,116,132,133,138,187,274 Diltiazem has been shown to inhibit metabolism of aminopyrine in vitro,132 and the drug has substantially reduced antipyrine clearance via apparent inhibition of oxidative metabolism in healthy adults.116,133

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.100,116,133,138,187,274

H2-Receptor Antagonists

Concomitant administration of diltiazem and cimetidine may result in increased plasma diltiazem concentrations.100,125,126,127 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).100,125 Concomitant administration of ranitidine produced some but not substantial alterations in these pharmacokinetic parameters of diltiazem.100,125,126,127 Cimetidine and ranitidine increased peak plasma deacetyldiltiazem concentrations by about 65 and 60%, respectively.125 Although the precise mechanism of this interaction is not known, cimetidine-induced inhibition of the cytochrome P-450 system may play a role;100,125,127 other mechanisms for the decreased clearance of diltiazem and its deacetyl metabolite also may be involved.125,127 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.100,126,127

Cyclosporine

Concomitant use of diltiazem and cyclosporine has resulted in increased blood cyclosporine concentrations112,113,237,297,298 and consequent cyclosporine-induced nephrotoxicity.112,297,298 Although further study is needed, it has been suggested that diltiazem may interfere with metabolism of cyclosporine via CYP3A4 inhibition.112,113 297 The possibility that diltiazem may increase serum cyclosporine concentrations and thereby increase its nephrotoxic potential should be considered if the drugs are used concomitantly.112,113 297,298 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.100,138,187,237,274,275,276,291,292,297,298

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%.138,200,201,202,203,204,205,206,207,208 Limited experience indicates that a similar interaction also may occur when verapamil, but not nifedipine, is administered concomitantly with carbamazepine.201,202,203,208 Although further study is needed, it has been suggested that diltiazem may inhibit hepatic metabolism of carbamazepine via CYP3A4.201,202,203,204,205,206,207,208 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.203 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.138,200,201,202,203,204,205,206,207,208

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.100,138,187,274,299,300 Although the exact mechanism has not been elucidated, diltiazem appears to inhibit the CYP3A4 isoenzyme responsible for metabolism of midazolam and triazolam.299,300 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).100,138,187,274 This interaction may result in increased adverse effects (e.g., prolonged sedation, respiratory depression) associated with the benzodiazepines.100,138,187,274,299,300

Buspirone

Concomitant use of diltiazem with buspirone may result in increased mean AUC and peak plasma concentrations of buspirone.100,138 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.100,138,187 The elimination half-life and time to peak plasma concentration of buspirone were not affected by diltiazem.100,138,187 This interaction may result in enhanced effects and increased adverse reactions associated with buspirone.100,138,187 In patients receiving buspirone concomitantly with diltiazem, dosage adjustment of buspirone may be necessary.100,138,187

Lovastatin

Concomitant use of diltiazem with lovastatin may result in increased mean AUCs and peak plasma concentrations of lovastatin and an increased risk of myopathy/rhabdomyolysis.100,138,187,274,302,600,602 This drug interaction was not observed when diltiazem was used concomitantly with pravastatin.100,138,187,274,302,600 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 (single dose of 20 mg) by 3- to 4-fold.274,301,302,600 When concomitant use is required, lovastatin therapy should be initiated at a dosage of 10 mg once daily and may be increased up to a maximum of 20 mg once daily.602 When a statin is required in a patient receiving diltiazem, a non-CYP3A4-metabolized statin should be used if possible.600 Patients receiving concomitant lovastatin concomitantly with diltiazem should be monitored for evidence of lovastatin toxicity (e.g., rhabdomyolysis, myositis).301,302

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.100,138,187 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%.100,138,187 Patients receiving quinidine concomitantly with diltiazem should be monitored for evidence of quinidine toxicity and quinidine dosage should be adjusted as necessary.100,138,187

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.304 In a clinical study, concomitant use of rifampin with diltiazem lowered the plasma diltiazem concentrations to undetectable levels.100,138,187,274 Concomitant use of diltiazem with rifampin (or any other known inducer of CYP3A4) should be avoided when possible and alternative therapy should be considered.100,138,187,274,304

Simvastatin

Concomitant use of simvastatin with diltiazem may result in increased systemic exposure to simvastatin and possible increased risk of myopathy and rhabdomyolysis.600,601 In a limited number of healthy individuals, administration of a single 20-mg dose of simvastatin in patients who had been receiving extended-release diltiazem 120 mg twice daily for 2 weeks resulted in a fivefold increase in mean simvastatin AUC.600,601 Based on computer simulations using these data, administration of diltiazem 480 mg once daily may be expected to result in an eightfold to ninefold increase in mean simvastatin AUC.600,601 When a statin is required in a patient receiving diltiazem, a non-CYP3A4-metabolized statin should be used if possible.600 When concomitant use is required, daily dosages of diltiazem and simvastatin should not exceed 240 and 10 mg, respectively. 600,601 Patients receiving simvastatin concomitantly with diltiazem should be monitored for evidence of simvastatin toxicity (e.g., rhabdomyolysis, myositis).600

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.318 Caution is advised if diltiazem and atazanavir are used concomitantly; a 50% reduction in diltiazem dosage and ECG monitoring also are recommended.318

Drugs Known to Impair Cardiac Contractility and Conduction

Concomitant use of diltiazem with drugs known to affect cardiac conduction or contractility may increase the risk of bradycardia, AV block, and heart failure.600

Beta-Adrenergic Blocking Agents

Concomitant use of diltiazem or other nondihydropyridine calcium-channel blockers with β-adrenergic blocking agents (β-blockers) can have additive negative effects on myocardial contractility, heart rate, and AV conduction.190,237,263,264,295 Although controlled studies indicate that concomitant use of diltiazem and a β-blocker 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-blockers may increase the sensitivity of the AV node to the direct depressant effects of diltiazem or other nondihydropyridine calcium-channel blocker.245,246,254,261,263,264 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 blocker mibefradil (no longer commercially available in the US), principally in geriatric patients and in association with concomitant β-blocker therapy.263,264

Diltiazem has been administered IV to patients maintained on oral β-blockers therapy, and the combination generally is well tolerated.237 However, the possibility of detrimental effects on myocardial contractility, heart rate, or AV conduction with such concomitant therapy should be considered.237 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.191 Because of the depressive effects of the drugs on myocardial contractility and AV conduction, IV diltiazem and IV β-blockers should not be administered within a few hours of each other.237

Oral bioavailability of propranolol has been increased by approximately 50% when diltiazem was administered concomitantly in several healthy individuals.100,138,187,237 Diltiazem has been shown to increase the mean plasma concentrations, elimination half-lives, AUC, and maximum plasma concentrations of propranolol or metoprolol.295,296 However, the mean plasma concentration and the pharmacokinetics of atenolol were not affected by concomitant use with diltiazem.295,296 In vitro, propranolol appears to be displaced from its binding sites by diltiazem.187,237 Dosage adjustment of propranolol may be necessary when concomitant diltiazem therapy is initiated or discontinued.100

General Anesthetics

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.100,138,187,237,274,323 When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully.100,138,187,237,274,323

Ivabradine

Concomitant use of diltiazem and ivabradine increases the systemic exposure of ivabradine and may exacerbate bradycardia and conduction disturbances.600 Concomitant use of ivabradine and diltiazem should be avoided.600

Nitrates

The manufacturers of diltiazem state that sublingual nitroglycerin may be administered as required during diltiazem therapy for relief of acute angina pectoris.100,187,323 The manufacturers also state that concomitant prophylactic therapy with short- or long-acting nitrates may be administered safely during diltiazem therapy,100,187,323 but that controlled studies to evaluate concomitant use of the drugs have not been performed.100

Other Drugs

Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in patients receiving diltiazem and clonidine concomitantly.600 Patients receiving such concomitant therapy should have their heart rate monitored.600

Acute Toxicity

Limited information is available on the acute toxicity of diltiazem.100 Because of the extensive metabolism of diltiazem, blood concentrations of the drug may vary tenfold.100,138,187 Therefore, the usefulness of such concentrations as a guide in the management of acute overdosages of diltiazem is limited.100,138,187

Acute overdosages of diltiazem (up to 18 g) have been reported.100,138,187 Fatalities as a result of these overdosages usually occurred in individuals who ingested diltiazem in combination with other drugs.100,138,187 Most patients with a known outcome recovered.100,138,187

Pathogenesis

The acute lethal dose of diltiazem in humans is not known,100,138,187 but blood concentrations greater than 800 ng/mL have not been associated with toxicity. The oral LD₅₀ of diltiazem hydrochloride is 415-740 and 560-810 mg/kg in mice and rats, respectively, and the IV LD₅₀ in these animals is 60 and 38 mg/kg, respectively.100,138,187 The oral LD₅₀ of diltiazem is greater than 50 mg/kg in dogs, and doses of 360 mg/kg are lethal in monkeys.100,138,187

Manifestations

Overdosage of diltiazem may be expected to produce signs and symptoms that are mainly extensions of common adverse reactions.100 Adverse effects observed following overdosage of diltiazem included bradycardia, hypotension, heart block, and heart failure.100,138,187,237

Treatment

If diltiazem overdosage or an exaggerated response to the drug occurs, general supportive and symptomatic treatment should be initiated in addition to gastric lavage and administration of activated charcoal.100,138,237,274 If bradycardia or second- or third-degree AV block occurs, IV atropine sulfate (0.6-1 mg) should be administered.100,138,187 If bradycardia and AV block do not respond to vagal blockade, isoproterenol hydrochloride may be administered with caution.100,138,187,237 Fixed second- or third-degree AV block should be treated with cardiac pacing.100,138,187 Sympathomimetic agents (e.g., isoproterenol, dopamine, dobutamine) and diuretics may be administered to treat cardiac failure.100,138 Ventilatory support also may be needed in some patients.138,187,274 Hypotension may be treated with fluids and a vasopressor agent (e.g., dopamine, levarterenol bitartrate, norepinephrine).100,138,187,274 IV calcium salts also may be useful for the management of hypotension, and possibly some other cardiovascular disturbances;117,118,120,121,122,123,124,128,129,130,131 however, use of IV calcium salts in the treatment of diltiazem overdosage has yielded conflicting results.100,138,187,274 In a few reported cases of calcium-channel blocker overdosage, hypotension and bradycardia that initially were refractory to atropine became more responsive to atropine following IV administration of calcium.100,138,187 In some cases, IV calcium (1 g calcium chloride or 3 g calcium gluconate) has been administered over 5 minutes and repeated every 10-20 minutes as needed.100,138,187 In addition, calcium gluconate has been administered by continuous IV infusion, at a rate of 2 g/hour for 10 hours;100,138,187 calcium infusions lasting 24 hours or more may be required.100,138,187 Patients receiving IV calcium should be monitored for signs of hypercalcemia.100,138,187 It appears that diltiazem is not eliminated by hemodialysis or peritoneal dialysis.100,138,237,274 Charcoal hemoperfusion has been used effectively, as adjunctive therapy, in eliminating diltiazem.190,237 Limited data suggest that plasmapheresis may hasten diltiazem elimination following overdosage.100,138,187,237

Pharmacology

Diltiazem has pharmacologic actions similar to those of other calcium-channel blockers (e.g., nifedipine, verapamil). The principal physiologic action of diltiazem is to inhibit the transmembrane influx of extracellular calcium ions across the membranes of myocardial cells and vascular smooth muscle cells, without changing serum calcium concentrations.

Calcium plays important roles in the excitation-contraction coupling processes of the heart and vascular smooth muscle cells and in the electrical discharge of the specialized conduction cells of the heart. The membranes of these cells contain numerous channels that carry a slow inward current and that are selective for calcium. Activation of these slow calcium channels contributes to the plateau phase (phase 2) of the action potential of cardiac and vascular smooth muscle cells.

The exact mechanism whereby diltiazem inhibits calcium ion influx across the slow calcium channels is not known, but the drug is thought to inhibit ion-control gating mechanisms of the channel, deform the slow channel, and/or interfere with the release of calcium from the sarcoplasmic reticulum.

By inhibiting calcium influx, diltiazem inhibits the contractile processes of cardiac and vascular smooth muscle, thereby dilating the main coronary and systemic arteries and decreasing myocardial contractility. In patients with Prinzmetal variant angina (vasospastic angina), inhibition of spontaneous and ergonovine-induced coronary artery spasm by diltiazem results in increased myocardial oxygen delivery. Dilation of systemic arteries by diltiazem results in a decrease in total peripheral resistance, a decrease in systemic blood pressure, a decrease in the afterload of the heart, and, at high doses (e.g., 210 mg), an increase in the cardiac index. Decreases in peripheral vascular resistance usually occur without orthostatic decreases in blood pressure or tachycardia; however, orthostatic hypotension has occurred occasionally when the upright position was assumed suddenly.138 The reduction in afterload, seen at rest and with exercise, and its resultant decrease in myocardial oxygen consumption, are thought to be responsible for the effects of diltiazem in patients with chronic stable angina pectoris. Diltiazem also appears to reduce left ventricular mass and wall thickness that are associated with hypertension.151,158,163,164,179

In contrast to nifedipine, diltiazem has substantial inhibitory effects on the cardiac conduction system, acting principally at the atrioventricular (AV) node, with some effects at the sinus node. When administered IV, diltiazem prolongs intranodal AV conduction and refractoriness, thereby prolonging the atria-His bundle (AH) interval; the drug usually has little or no effect on the His-Purkinje conduction system or intra-atrial or intraventricular conduction. Diltiazem increases AV nodal refractoriness by binding to calcium channels; binding is enhanced during depolarization, and the drug tends to unbind in a time-dependent manner during repolarization. Therefore, when heart rate is increased (e.g., tachycardia), calcium channel-bound diltiazem reportedly increases as a result of a greater number of depolarizations (allowing drug binding) and shorter diastolic periods (limiting drug unbinding). This frequency-dependent effect of diltiazem on AV nodal conduction allows it to selectively decrease heart rate during tachyarrhythmias involving the AV node while having little or no effect on normal AV nodal conduction at normal heart rates. Although diltiazem rarely produces clinically important changes in the rate of sinoatrial (SA) node discharge or recovery time, in patients without SA node dysfunction, the drug may decrease heart rate and prolong sinus cycle length, and may produce sinus arrest or sinus block in patients with SA node disease (e.g., sick sinus syndrome). Diltiazem has little effect on the QT interval and does not affect the His-Purkinje conduction system. In patients with paroxysmal supraventricular tachycardia (PSVT), including AV nodal reentrant tachycardias and reciprocating tachycardias associated with extranodal accessory pathways (e.g., Wolff-Parkinson-White [WPW] syndrome, short PR syndrome), the drug's effect at the AV node results in an interruption of conduction along the reentrant pathway and restoration of normal sinus rhythm. Similarly, diltiazem's effect on the AV node reduces rapid ventricular response rate (generally 150 bpm) caused by atrial flutter or atrial fibrillation. However, the drug does not prolong the refractoriness of the accessory pathway in patients with atrial flutter or fibrillation associated with an accessory pathway (e.g., WPW syndrome, short PR syndrome); these patients may experience a potentially life-threatening increase in heart rate accompanied by hypotension.

Although negative inotropic effects have been noted in vitro and in animal studies with diltiazem, they are rarely seen clinically. Major increases in left ventricular end-diastolic pressure (LVEDP) or volume (LVEDV) or decreases in cardiac ejection fraction usually are not seen following diltiazem administration in patients with normal ventricular function. However, worsening of congestive heart failure has been reported in patients with impaired ventricular function.138,274

Diltiazem does not appear to affect blood glucose, serum insulin, and plasma renin or aldosterone concentrations.142,152,154,157,188,191,192,193 Following oral administration of diltiazem in hypertensive patients, serum total cholesterol, high- (HDL) and low-density lipoprotein (LDL)-cholesterol, and triglyceride concentrations have generally been unchanged.154,157,188,191,192,193 In patients with hypertension, diltiazem generally does not change renal plasma flow or glomerular filtration rate while it decreases renal vascular resistance; the drug does not cause sodium or water retention.162,188,191,194

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;138,179,180 however, peak plasma concentration at steady state is lower and the time to peak concentrations is longer with extended-release capsules.179 The oral bioavailability of diltiazem from Cardizem^® CD extended-release capsules at steady state is about 95% when compared with that of conventional diltiazem hydrochloride tablets.187 Oral bioavailability of diltiazem hydrochloride increases disproportionately with increasing doses;100,138,179,190,275 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.100,138,179,187,274 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%.323

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;187,323,325 however, rate of absorption may be increased if the extended-release capsules (Tiazac^®, Taztia XT^®) are taken with a high-fat meal.274,326 Food may affect extent of absorption of some extended-release diltiazem hydrochloride capsules (Dilt-XR^®); AUC was increased by 13 or 19%, while peak plasma concentrations increased by 37 or 51%, when Dilt-XR^® extended-release capsules were administered with a high-fat meal.601 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.275

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). 323 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.242 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.239 After continuous IV infusion at a rate of 10 mg/hour in healthy adults, steady-state plasma diltiazem concentrations average approximately 160 ng/mL.242

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.188 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.237,239,245 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.237,247,252 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.237,246,247,252 Blood pressure reductions following direct IV injection of diltiazem, if they occur, generally are short-lived but may last 1-3 hours.237 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.191,248,250 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.237,239,241,242,245,248,256,259 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.237,242 No consistent relationship has been established between plasma diltiazem concentrations or dosage and overall blood pressure reduction in healthy adults.191,239,243,244,246,256

Distribution

Diltiazem has a large volume of distribution because of its lipophilicity and is rapidly and extensively distributed into body tissues.191,245,259 The extensive distribution also may be secondary to the relatively high unbound fraction in plasma.259 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.237,242 About 70-85% of diltiazem is bound to plasma proteins, but only 30-40% is bound to albumin.135,237,259

Diltiazem is distributed into milk, apparently in concentrations approximately equal to maternal serum concentrations.100,101,237

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.191,237 Half-life may be slightly prolonged after multiple oral dosing.191 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.135,237,259 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.191,237 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.237,239,242 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.191,237,239 Plasma half-life of the drug may be increased in geriatric patients, but is unchanged or only slightly increased in patients with renal impairment.191,237,239 Liver cirrhosis has been shown to reduce diltiazem's apparent oral clearance and to prolong its half-life.237

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.100,132,134,135,136,137,182,183,237,241,242 Plasma diltiazem concentrations are higher following multiple oral doses of the drug than after single oral doses, indicating saturation of hepatic microsomal enzyme systems.135,245 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.237,239,241,242 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.135,239,242 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.239 However, data from a study in healthy individuals indicate the presence of appreciable concentrations of active metabolites following continuous IV infusion of the drug.242 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.237

Approximately 2-4% of a dose of the drug is excreted in urine unchanged.135,237,259 The remainder of the drug is eliminated in urine and via bile, mainly as metabolites.

Chemistry and Stability

Chemistry

Diltiazem is a benzothiazepine-derivative calcium-channel blocker. Because most currently available calcium-channel blockers are dihydropyridines, diltiazem, like verapamil and mibefradil (no longer commercially available in the US), has been referred to as a nondihydropyridine calcium-channel blocker. Diltiazem is commercially available as diltiazem hydrochloride oral extended-release138,187,188,189,190,274,290 capsules, extended-release tablets,323 conventional tablets,100 and parenteral injections and powder for injection.237,293 Diltiazem also has been commercially available as diltiazem malate extended-release tablets275 and diltiazem malate extended-release tablets in fixed combination with enalapril; however, these preparations are no longer commercially available in the US.276 Diltiazem hydrochloride occurs as a bitter-tasting, white to off-white crystalline powder that is soluble in water and alcohol.100,138,187,189,190,237,274,278,323 Diltiazem malate occurs as a white to off-white crystalline powder that is soluble in water and slightly soluble in alcohol.275,276,280

USP temporarily stated that potency of diltiazem hydrochloride preparations should be expressed both in terms of the salt and the base (“active moiety”).185,186 However, USP recently reverted to its previous standard that potency be expressed only in terms of diltiazem hydrochloride.236 Dosage of diltiazem hydrochloride currently is expressed in terms of diltiazem hydrochloride.179 Therefore, care should be taken to avoid confusion between potencies that during a transitional period may be labeled as the salt and/or base and dosage of diltiazem hydrochloride.186

Diltiazem hydrochloride injection is a clear, colorless, nonpyrogenic, sterile solution of the drug in sorbitol and water for injection.237 Hydrochloric acid or sodium hydroxide may be added to the solution during manufacture to adjust the pH to 3.7-4.1.237 Diltiazem hydrochloride powder for IV infusion in ADD-Vantage^® vials contains mannitol.332

Each extended-release diltiazem hydrochloride capsule (Dilt-XR^®) consists of multiple 60-mg tablets contained in a swellable matrix core that slowly releases the drug over approximately 24 hours.189,324 The commercially available Cardizem^® CD extended-release diltiazem capsules contain 2 types of beads of diltiazem hydrochloride; the beads differ in the thickness of their copolymer membranes that surround the beads.188,290 In Cardizem^® CD extended-release capsules 40% of the beads (surrounded by the thinner copolymer membrane) release the drug within 12 hours of oral administration of the extended-release diltiazem hydrochloride capsules and 60% of the beads (surrounded by the thicker copolymer membrane) release the drug throughout the last 12 hours of a 24-hour period following oral administration of these extended-release capsules.188,290 The manufacturer states that Cardizem^® CD extended-release capsules and Cardizem^® LA extended-release tablets provide continuous therapeutic plasma concentrations of diltiazem over a 24-hour period.188,290,323

Stability

Unless otherwise specified by the manufacturer, diltiazem hydrochloride conventional tablets, extended-release capsules, and extended-release tablets should be stored in tight, light-resistant, containers at a controlled room temperature of 25°C but may be exposed to temperatures ranging from 15-30°C; excessive humidity should be avoided.100,138,187,323

Diltiazem hydrochloride injection in vials should be refrigerated at 2-8°C; freezing of the injection should be avoided.237 Diltiazem hydrochloride injection may be stored at room temperature for up to 1 month; after that time, the injection should be discarded.237 Diltiazem hydrochloride powder for IV infusion in ADD-Vantage^® vials should be stored at a room temperature of 20-25°C; freezing of the powder for IV infusion should be avoided.332

In concentrations up to 1 mg/mL, diltiazem hydrochloride-containing solutions are stable for at least 24 hours at controlled room temperature (15-30°C) or under refrigeration at 2-8°C, when stored in glass or polyvinyl chloride (PVC) bags in the following IV infusions: 0.9% sodium chloride, 5% dextrose, or 5% dextrose and 0.45% sodium chloride injection.237 The manufacturers state that, for IV infusion, diltiazem hydrochloride injection should be diluted to a final concentration of 0.45, 0.83, or 1 mg/mL by adding 250, 250, or 125 mg of diltiazem hydrochloride to 500, 250, or 100 mL, respectively, of a compatible IV infusion solution;237 these IV infusion solutions should be stored at room temperature or under refrigeration until administration and used within 24 hours.237

After the ADD-Vantage^® vials containing diltiazem hydrochloride 100 mg have been connected to an appropriate diluent container (containing 100 mL of 0.9% sodium chloride or 5% dextrose injection) and activated for dilution, the resultant 1-mg/mL solution is stable for 24 hours at controlled room temperature (15-30°C) or under refrigeration at 2-8°C;332 these IV infusion solutions should be stored at room temperature or under refrigeration until administration and used within 24 hours.332

Diltiazem hydrochloride is potentially physically incompatible with many drugs, including acetazolamide, acyclovir, aminophylline, ampicillin, ampicillin sodium in fixed combination with sulbactam sodium, cefamandole, cefoperazone, diazepam, furosemide, heparin, hydrocortisone sodium succinate, insulin (regular; 100 units/mL), methylprednisolone sodium succinate, mezlocillin, nafcillin, phenytoin, rifampin, and sodium bicarbonate.237,249 Specialized references should be consulted for specific compatibility information.249

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer's labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

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