Diltiazem hydrochloride is a nondihydropyridine calcium-channel blocking agent (calcium-channel blocker).100, 187, 274, 323, 324, 325, 600, 601, 603, 703, 1310
Diltiazem is used in the management of angina, including chronic stable angina and angina due to coronary artery spasm (e.g., Prinzmetal variant angina).100, 187, 274, 323, 324, 325, 600, 601, 1303 Various oral preparations of diltiazem (immediate-release tablets, extended-release capsules, extended-release tablets) are available for this use.100, 187, 274, 323, 324, 325, 600, 601
Safety and efficacy of diltiazem in adults with angina have been established in several double-blind, placebo-controlled, dose-response studies that measured the impact of the drug on exercise tolerance, nitroglycerin consumption, and anginal frequency.187, 274, 323, 324, 325, 600 Increased time to termination of exercise, utilizing a Bruce exercise protocol and measured at diltiazem trough, was observed following administration of diltiazem extended-release capsules (Cardizem® CD, Cartia XT®) 60-480 mg once daily.187, 325 Improvement in time to termination of exercise was 29, 40, 56, 51, 69, and 68 seconds for the placebo, diltiazem 60, diltiazem 120, diltiazem 240, diltiazem 360, and diltiazem 480 mg treatment groups, respectively.187, 325 Overall angina frequency decreased as doses increased.187, 325 A significant increase in time to termination of exercise and a significant decrease in overall angina frequency were observed in a second double-blind study of patients administered diltiazem extended-release capsules (Cardizem® CD, Cartia XT®) 180 mg or placebo once daily with concomitant long-acting nitrates and/or beta-adrenergic blocker treatment.187, 325
In patients with chronic stable angina, increased exercise tolerance relative to baseline, utilizing a Bruce exercise protocol and measured at diltiazem trough or peak (8 hours after dosing), was observed following administration of diltiazem extended-release capsules (Tiazac®or Tiadylt® ER) 120-540 mg once daily.274, 601 Improvement in exercise tolerance at trough was 14 seconds for placebo and 26, 41, 33, and 32 seconds over baseline for the diltiazem 120-, 240-, 360-, and 540-mg treatment groups, respectively.274, 601 Statistically significant improvement in exercise tolerance at peak (8 hours after dosing) was 13, 38, 64, 55, and 42 seconds over baseline for the placebo and diltiazem 120-, 240-, 360-, and 540-mg treatment groups, respectively.274, 601 Statistically significant reductions in anginal attacks and decreased nitroglycerin requirements compared with baseline were also observed in diltiazem-treated patients compared with placebo-treated patients.274, 601
In patients with chronic stable angina, increased exercise tolerance was observed 21 hours after evening administration of diltiazem extended-release tablets (Cardizem® LA, Matzim® LA) at doses of 180, 360, and 420 mg.323, 600 The placebo-subtracted mean effect was 20-28 seconds for all 3 doses evaluated, with no dose-response demonstrated.323, 600 Exercise tolerance was increased when measured 25 hours after administration of diltiazem extended-release tablets 360 mg given in the morning; as expected, this effect was smaller than the effects measured only 21 hours following nighttime administration.323, 600 A larger effect to increased exercise tolerance occurred at peak versus trough serum concentrations.323, 600
In patients with chronic angina, dose-related increases in exercise time (measured by Exercise Tolerance Test) and reductions in rates of anginal attacks (based on individual patient diaries) were observed following administration of Dilt-XR® extended-release capsules 120, 240, or 480 mg once daily.324 Improvement in total exercise time (using the Bruce protocol), measured at trough exercise periods, was 20, 37, 49, and 56 seconds for the placebo, 120 mg diltiazem, 240 mg diltiazem, and 480 mg diltiazem groups, respectively.324
The 2023 American Heart Association/American College of Cardiology (AHA/ACC) clinical practice guideline for the management of patients with chronic coronary disease addresses the treatment of patients with stable angina symptoms (or ischemic equivalents).1303 The practice guideline recommends the use of beta-adrenergic blocking agents, calcium-channel blocking agents, or long-acting nitrates for relief of angina or equivalent symptoms in patients with chronic coronary disease.1303 The goal of therapy is to maximize relief of symptoms of angina without exacerbating comorbidities or adverse effects.1303
Selection of drug therapy should be individualized and consider comorbid conditions, which may justify the use of one agent over another.1303 Calcium-channel blockers (used alone or in combination with nitrates) are considered first-line for the management of vasospastic angina.1303 In patients with microvascular angina (nonobstructive coronary artery disease), calcium-channel blockers may be used second-line when beta-adrenergic blockers are not tolerated or are ineffective.1303 Nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) should not be used in patients with significant left ventricular dysfunction.1303 Due to an increased potential for synergistic induction or exacerbation of bradycardia and left ventricular dysfunction, nondihydropyridine calcium-channel blockers should be used with caution in patients receiving beta-adrenergic blockers.1303 In patients with angina refractory to a single agent, symptom control may be improved by the addition of a second agent (i.e., addition of a long-acting nitrate to a calcium-channel or beta-adrenergic blocking agent).1303
Diltiazem is used alone or in combination with other classes of antihypertensive agents in the management of hypertension.187, 274, 323, 324, 325, 600, 601, 603, 1200 Various oral preparations of diltiazem (extended-release capsules [once-a-day or twice-a-day]; extended-release tablets [once-a-day]) are available for this use.187, 274, 323, 324, 325, 600, 601, 603
Safety and efficacy of diltiazem in adults with hypertension have been established in several double-blind, placebo-controlled, dose-response studies that measured the antihypertensive effects of the drug in patients with mild to moderate hypertension.187, 274, 323, 324, 325, 600, 601
Supine diastolic blood pressure decreased in an apparent linear manner following administration of diltiazem extended-release capsules (Cardizem® CD, Cartia XT®) 90-540 mg once daily.187, 325 The change in diastolic blood pressure measured at trough for placebo, diltiazem 90 mg, diltiazem 180 mg, diltiazem 360 mg, and diltiazem 540 mg was -2.9, -4.5, -6.1, -9.5, and -10.5 mm Hg, respectively.187, 325
Supine diastolic, standing diastolic and systolic blood pressures decreased in a statistically significant linear manner following administration of diltiazem extended-release capsules (Tiazac®or Tiadylt® ER) for 4 weeks in patients with mild to moderate hypertension.274, 601 The change in diastolic blood pressure measured at trough (24 hours after the dose) for placebo, diltiazem 90 mg, diltiazem 180 mg, diltiazem 360 mg, and diltiazem 540 mg was -5.4, -6.3, -6.2, -8.2, and -11.8 mm Hg, respectively.274, 601 Blood pressures were reduced in a linear manner in another study evaluating diltiazem extended-release capsules (Tiazac®).274, 601 Supine diastolic blood pressure measured following 2-week intervals of treatment was reduced by --3.7 mm Hg with diltiazem 120 mg versus -2.0 mm Hg with placebo, by -7.6 mm Hg with diltiazem 240 mg versus -2.3 mm Hg with placebo, by -8.1 mm Hg with diltiazem 360 mg versus -0.9 mm Hg with placebo, and by -10.8 mm Hg with diltiazem 480 mg or 540 mg versus -2.2 mm Hg with placebo.274, 601
Reductions in diastolic blood pressure (measured by ambulatory monitoring) at roughly 24 hours after morning (4-8 AM) or evening (6-10 PM) administration (i.e., the time corresponding to expected trough serum concentrations) of diltiazem were observed in a randomized, double-blind, parallel-group, dose-response study involving 478 patients.323, 600 Following administration of diltiazem extended-release tablets (Cardizem® LA, Matzim® LA) 120 mg, 240 mg, 360 mg, or 540 mg in the evening and 360 mg administered in the morning, mean change in trough diastolic blood pressure was -2.0, -4.4, -4.4, and -8.1, and -6.4 mm Hg, respectively.323, 600 In a similar study, apparently linear mean reductions in diastolic blood pressure (measured by supine office cuff sphygmomanometer) at trough (7-9 AM) were observed over the dosage range studied.323, 600 Following morning administration of placebo or diltiazem extended-release tablets (Cardizem® LA, Matzim® LA) 120 mg, 180 mg, 300 mg, or 540 mg, group mean changes in trough diastolic blood pressure were -2.6, -1.9, -5.4, -6.1, and -8.6 mm Hg, respectively.323, 600
Among patients with mild to moderate hypertension, statistically significant dose-related reductions in mean supine systolic and diastolic blood pressures were observed through 4 weeks of treatment with once daily Dilt-XR® extended-release capsules.324 Decreases in trough mean diastolic and systolic blood pressures were -5.1 and -2.6 mm Hg, respectively, with diltiazem 120 mg, -6.9 and -6.5 mm Hg, respectively, with diltiazem 240 mg, -6.9 and -4.8 mm Hg, respectively, with diltiazem 360 mg, and -10.6 and -10.6 mm Hg, respectively with diltiazem 480 mg.324 The proportion of evaluable patients exhibiting a therapeutic response (supine diastolic blood pressure <90 mm Hg or decrease >10 mm Hg) was 31, 42, 48, and 69% with diltiazem 120, 240, 360, and 480 mg, respectively.324 The antihypertensive effect at trough (24 hours after a dose) was more than one-half of the response seen at peak (3-6 hours after Dilt-XR® extended-release capsule administration).324
Mean supine blood pressures were reduced in patients with mild to moderate hypertension in another clinical trial with diltiazem (Dilt-XR®) extended-release capsules.324 Blood pressures were lower following 2 weeks of treatment with diltiazem 180 mg daily (diastolic: -6.1 mm Hg; systolic: -4.7 mm Hg) and again, 2 weeks after escalation to 360 mg daily (diastolic: -9.3 mm Hg; systolic: -7.2 mm Hg).324 However, additional increase in dosage to 540 mg daily for 2 weeks provided only minimal further increase in the antihypertensive effect (diastolic: -10.2 mm Hg; systolic: -6.7 mm Hg).324
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 failure329, 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
The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.1200, 1300 The relationship between blood pressure and cardiovascular disease is continuous, consistent, and independent of other risk factors.1200, 1300 The higher the blood pressure, the more likely the development of coronary artery disease, heart failure, stroke, and chronic kidney disease across all ages and ethnic groups.1200, 1300 Each 20-mm Hg increment in systolic blood pressure or 10-mm Hg increment in diastolic blood pressure has been shown to double the risk of death from stroke, heart disease, or other vascular disease.171, 1200, 1300
Accurate blood pressure measurement in the office or clinic is essential for proper diagnosis and management of hypertension.1200, 1300, 1302 Out-of-office blood pressure measurements are recommended to confirm the diagnosis of hypertension.1200 Blood pressure categories range from normal to different grades/stages of hypertension and are intended to align therapeutic approaches with blood pressure levels.1300, 1302 According to most major guidelines, hypertension is diagnosed when systolic blood pressure is ≥140 mm Hg and/or diastolic blood pressure is ≥90 mm Hg as measured in the office or clinic.1300, 1302 Some guidelines consider a systolic blood pressure of 130-139 mm Hg and/or a diastolic blood pressure of 80-89 mm Hg to be stage 1 hypertension,1200 whereas other guidelines consider this a high-normal blood pressure; however, treatment recommendations are generally the same (i.e., nonpharmacologic therapy with consideration of pharmacologic therapy based on cardiovascular risk).1200, 1300, 1302
Comprehensive guidelines for the management of hypertension have been published by various authoritative groups.501, 1200, 1300, 1301, 1302 The first such guideline was published by the National Heart Lung and Blood Institute (NHLBI) in 1977, followed by a series of Joint National Committee (JNC) guidelines with JNC8 being the last iteration of these guidelines in 2014.501, 1200 The American College of Cardiology (ACC), American Heart Association (AHA), and other experts, including the International Society of Hypertension (ISH), have published more recent clinical practice guidelines for the treatment of hypertension.1200, 1300, 1302 These guidelines all state that lifestyle/behavioral modifications (e.g., weight reduction in patients who are overweight or obese, dietary changes, sodium reduction, potassium supplementation, increased physical activity, moderation of alcohol intake, smoking cessation) are essential in the management of hypertension and should be implemented as first-line therapy to lower blood pressure and reduce total cardiovascular risk.1200, 1300, 1302 The decision whether to initiate antihypertensive drug therapy should be based on the office blood pressure level while also considering cardiovascular risk factors.1200, 1219, 1300, 1302 Most guidelines agree that antihypertensive drug treatment should be offered in addition to lifestyle modifications to patients with grade 2 (blood pressure 160-179/100-109 mm Hg) or grade 3 (systolic blood pressure ≥180/110 mm Hg) hypertension; however, there is some controversy regarding whether patients with grade 1 hypertension (blood pressure 140-159/90-99) should be treated with antihypertensive drug therapy.1200, 1300, 1302 Some guidelines recommend immediate drug treatment in patients with grade 1 hypertension (blood pressure 140-159/90-99) who have high cardiovascular risk or comorbid conditions (cardiovascular disease, chronic kidney disease, diabetes mellitus or hypertension-mediated organ damage) and a trial of lifestyle intervention first in those with low to moderate cardiovascular risk who do not have these comorbid conditions,1302 whereas other guidelines recommend that all hypertensive patients including those with grade 1 hypertension receive blood pressure-lowering treatment, irrespective of their cardiovascular risk.1300 In some guidelines, drug treatment is recommended in patients with blood pressure in the high-normal range (≥130/80 mm Hg) who have cardiovascular disease.1200, 1210, 1300
Current evidence-based practice guidelines for the management of hypertension in adults generally recommend the use of drugs from 4 classes of antihypertensive agents (angiotensin-converting enzyme [ACE] inhibitors, angiotensin II receptor antagonists, calcium-channel blockers, and thiazide or thiazide-like diuretics); data from clinical outcome trials indicate that lowering blood pressure with any of these drug classes can reduce the complications of hypertension and provide similar cardiovascular risk reduction benefits. 501, 503, 1200, 1300, 1302 However, recommendations for initial drug selection and use in specific patient populations may vary across these guidelines.501, 503, 1200 This variability is due, in part, to differences in the guideline development process and the types of studies included in the evidence reviews (e.g., randomized controlled studies only versus a range of studies with different study designs).501, 503, 1200 Ultimately, choice of antihypertensive therapy should be individualized, considering the clinical characteristics of the patient (e.g., age, ethnicity/race, comorbid conditions, cardiovascular risk factors), as well as drug-related factors (e.g., ease of administration, availability, adverse effects, costs).501, 503, 510, 1200, 1300, 1302 Calcium-channel blockers may be particularly useful in the management of hypertension in black patients; these patients tend to have a 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).316, 317, 327, 328, 501, 1200 Use of a calcium-channel blocker also may be beneficial in patients with certain coexisting conditions such as ischemic heart disease (e.g., angina) and in geriatric patients, including those with isolated systolic hypertension.510, 1200 Other antihypertensive drugs, such as beta blockers, direct vasodilators, alpha-1 blockers, loop diuretics, and aldosterone antagonists, are available, but generally recommended as second-line agents or only in specific clinical situations.1200
Because most patients with hypertension will require at least 2 antihypertensive drugs to achieve adequate blood pressure control, use of single pill combinations are generally recommended when available.1302 Drug regimens with complementary activity, where a second antihypertensive agent is used to block compensatory responses to the first agent or affect a different pressor mechanism, can result in additive blood pressure lowering and are preferred.1200 Drug combinations that have similar mechanisms of action or clinical effects (e.g., the combination of an ACE inhibitor and an angiotensin II receptor antagonist) generally should be avoided.1200 Antihypertensive drug dosages should be adjusted and/or other agents substituted or added until goal blood pressure is achieved.1200 After initiation of antihypertensive drug therapy, a blood pressure goal of less than 130/80 mm Hg within 3 months is generally recommended if tolerated, but should be individualized.1200, 1301, 1302 While there is evidence from a randomized controlled study (SPRINT) demonstrating that intensive systolic blood pressure lowering (to <120 mm Hg) may be beneficial in patients with increased risk of cardiovascular disease, the study excluded patients with diabetes mellitus or prior stroke, and those younger than 50 years of age, which may decrease the generalizability of these findings.1210, 1219
Specific guidelines for the management of hypertension in pregnancy have been published by experts such as AHA and the American College of Obstetrics and Gynecologists (ACOG).1305, 1306 First-line oral antihypertensive drugs generally recommended in pregnant patients include labetalol, nifedipine (extended-release), or methyldopa.1200, 1302, 1305 Other oral dihydropyridine calcium-channel blockers such as nicardipine or amlodipine may also be considered.1302, 1304, 1305 In patients requiring immediate blood pressure lowering (i.e., eclampsia, HELLP [preeclampsia/hemolysis, elevated liver enzymes and low platelets]), IV labetalol, nicardipine, or magnesium sulfate may be used.1300, 1302 Renin-angiotensin system (RAS) blockers (e.g., ACE inhibitors, angiotensin receptor blockers, direct renin inhibitors) are contraindicated during pregnancy due to adverse fetal and neonatal outcomes.1200, 1300, 1302, 1305
Diltiazem is used in the management of adults with supraventricular tachycardias (SVTs), including rapid conversion to sinus rhythm of paroxysmal supraventricular tachycardia (PSVT) (e.g., tachycardia associated with Wolff-Parkinson-White or short PR syndrome), and control of rapid ventricular rate in atrial flutter or fibrillation. 238, 239, 247, 250, 252, 253, 256, 257, 258, 262, 332, 700, 703, 706
Paroxysmal Supraventricular Tachycardia
IV diltiazem is used for rapid conversion of PSVT that is uncontrolled or unconverted by vagal maneuvers, including atrioventricular nodal reentrant tachycardias and PSVT associated with extranodal accessory pathways (e.g., Wolff-Parkinson-White or short PR syndrome).250, 256, 332, 700, 703, 706 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, 238, 250, 256, 332, 703, 706 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.250, 332, 703
Oral diltiazem† also has been used for the ongoing management of PSVT, but efficacy of the drug for this condition has not been established.248, 260, 700
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 vagal maneuvers, adenosine, IV beta-adrenergic blockers, or IV nondihydropyridine calcium-channel blockers for acute treatment.700 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, an IV nondihydropyridine calcium-channel blocker (e.g., diltiazem or verapamil) or IV beta-adrenergic blocker (e.g., esmolol, metoprolol) may be considered.700 Nondihydropyridine calcium-channel blockers (e.g., diltiazem or verapamil) should only be used in hemodynamically stable patients who do not have impaired ventricular function.700 Oral nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) are recommended for the ongoing management of these arrhthymias.700
While trials comparing IV diltiazem and verapamil have not been performed, the efficacy rate of IV diltiazem in converting PSVT to sinus rhythm appears to be similar to that of verapamil191, 238, 252, 257 however experts state diltiazem may be associated with fewer adverse events (e.g., hypotension).1313, 1314
Atrial Fibrillation and Flutter
IV diltiazem is used for temporary control of rapid ventricular rate in atrial flutter or fibrillation.703, 706 Drugs that block AV nodal conduction (e.g., diltiazem, verapamil) 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 short PR syndrome) or with preexcited ventricular complexes or wide QRS complexes, since ventricular tachyarrhythmias, including ventricular fibrillation and cardiac arrest, may be precipitated.191, 261, 262, 1307 Although approximately 95% of patients with atrial flutter or fibrillation respond to direct IV injection of 1 or 2 diltiazem 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.191, 238, 252, 332, 703, 706
The safety and efficacy of continuous IV diltiazem infusion for 24-hour acute heart rate control in patients with atrial flutter or fibrillation were evaluated in a randomized, double-blind, placebo-controlled trial in a limited number of patients.1307 Therapeutic response was maintained for 24 hours in 74% (17/23) or 0% (0/21) of patients treated with diltiazem or placebo, respectively.1307 Patients who received diltiazem infusion lost response significantly more slowly than those who received placebo over the 24-hour period.1307
In another study comparing IV diltiazem, digoxin, and amiodarone for acute rate control in patients with atrial flutter or fibrillation, time to rate control was significantly shorter among patients in the diltiazem group; the percentage of patients who achieved rate control was higher in the diltiazem group (90%) compared with the digoxin group (74%) and the amiodarone group (74%).1307
Pharmacokinetic data indicate that diltiazem has a faster onset of action than digoxin.258 In a small randomized controlled study in 30 patients with atrial fibrillation and a rapid ventricular response, treatment with IV diltiazem significantly decreased heart rate within 5 minutes compared with 3 hours with IV digoxin.258, 1307
Oral diltiazem also has been used for rate control in patients with atrial fibrillation† and a left ventricular ejection fraction greater than 40%.1307 A limited number of patients with permanent atrial fibrillation requiring rate control were evaluated in a prospective, randomized, cross-over trial.1307 The 24-hour heart rate (measured using Holter monitoring) was 96 beats/minute at baseline (no treatment), and 75, 81, 82, or 84 beats/minute after 3 weeks of treatment with diltiazem 360 mg/day, verapamil 240 mg/day, metoprolol 100 mg/day, or carvedilol 25 mg/day, respectively.1308 All drugs reduced heart rate compared with baseline; diltiazem reduced heart rate significantly more than with any other drug.1307, 1308 There was no difference in all-hospitalization and all-cause mortality among patients receiving monotherapy for rate-control with beta-adrenergic blockers, nondihydropyridine calcium-channel blockers or digoxin in the AFFIRM (Atrial Fibrillation Follow-up Investigation of Rhythm Management) trial.1307
The 2023 American College of Cardiology/American Heart Association/American College of Clinical Pharmacy/Heart Rhythm Society (ACC/AHA/ACCP/HRS) guideline for the management of adults with atrial fibrillation recommend nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) or beta-adrenergic blockers for acute and long-term ventricular rate control in patients with nonpreexcited atrial fibrillation or flutter.1307 In patients with atrial fibrillation with rapid ventricular response who are hemodynamically stable, IV beta-adrenergic blockers or nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) are recommended for acute rate control.1307 Beta-adrenergic blockers or nondihydropyridine calcium-channel blockers (i.e., diltiazem, verapamil) are also recommended for long-term rate control in patients with nonpreexcited atrial fibrillation.1307 Nondihydropyridine calcium-channel blockers should not be administered in patients with comorbid left ventricular ejection fraction (LVEF) <40%.1307 Cardioversion is indicated in hemodynamically unstable patients.1307 There are limited data comparing various rate control agents; selection of specific agents should consider patient-specific characteristics (e.g., reduced ejection fraction heart failure, reactive airway disease) and response.1307
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 has been 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
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
Pulmonary Arterial Hypertension
Diltiazem has been used in the management of pulmonary arterial hypertension (PAH)†.1309 Expert consensus guidelines on treatment of PAH in adults state that a calcium-channel blocker may be used to treat patients with PAH who have demonstrated acute vasoreactivity according to consensus definition, who do not have contraindications to calcium-channel blocker therapy, and who do not have right-sided heart failure.1309 Long-acting nifedipine or diltiazem, or amlodipine are suggested; verapamil should be avoided due to its potential negative inotropic effects.1309 Patients should be closely followed for safety and efficacy with reassessment at 3 months; alternative or additional drug therapy should be instituted if the patient does not improve to WHO functional class I or II.1309
Diltiazem has been used in the management of patients with hypertrophic cardiomyopathy (HCM)†.1315 Expert guidelines recommend nonvasodilating beta-adrenergic blockers, titrated to effectiveness (i.e., suppression of resting heart rate) or maximally tolerated doses, to provide relief of symptoms in patients with obstructive HCM and symptoms attributable to left ventricular outflow tract obstruction (e.g., effort-related dyspnea or chest pain and occasionally other exertional symptoms, such as syncope or near syncope that interfere with everyday activity or quality of life).1315 In such patients not responding to or intolerant of beta-adrenergic blocker therapy, a nondihydropyridine calcium-channel blocker (e.g., diltiazem, verapamil) is recommended.1315 Based on limited data, nondihydropyridine calcium-channel blockers (e.g., diltiazem, verapamil) may provide relief of symptoms in patients with obstructive HCM, however the negative inotropic and negative chronotropic effects of such drugs may be limiting.1315 Nondihydropyridine calcium-channel blockers or beta-adrenergic blockers are also recommended in patients with nonobstructive HCM with preserved ejection fraction and symptoms of exertional angina or dyspnea.1315
Diltiazem has been used in the management of radial artery spasm†, a complication of transradial artery access (TRA) for percutaneous coronary angiography.1318 The American Heart Association (AHA) recommends the use of intra-arterial (IA) calcium channel blockers (i.e., diltiazem 2.5-5 mg, verapamil 2.5-5 mg, nicardipine 250-500 mcg) or nitroglycerin 100-200 mcg to reduce radial artery spasm.1318 The drug should be administered after sheath insertion, and possibly with each catheter exchange or before sheath removal.1318 In a randomized study (SPASM3), patients receiving IA verapamil 2.5 mg or isosorbide dinitrate 1 mg (not available in the US) compared with diltiazem 5 mg before transradial coronary intervention experienced a lower incidence (16.2, 17.2, and 26.6%, respectively) of radial artery spasm.1320
Diltiazem has been used in the management of thyrotoxicosis†.1316 Expert guidelines for the management of hyperthyroidism recommend diltiazem or verapamil in patients unable to tolerate or who are not candidates for beta-adrenergic blocking agents (e.g., bronchospastic asthma) for heart rate control, especially elderly patients and thyrotoxic patients with resting heart rates >90 beats per minute or coexistent cardiovascular disease with symptomatic thyrotoxicosis.1316
Diltiazem has been used in the management of acute aortic syndromes (AAS)†.1336 The American College of Cardiology/American Heart Association (ACC/AHA) guidelines recommend IV antihypertensive therapy for the management of AAS, including, but not limited to, aortic dissection.1336 IV beta-adrenergic blockers are recommended first-line for initial blood pressure and heart rate management in patients with AAS.1336 IV nondihydropyridine calcium channel blockers (e.g., diltiazem, verapamil) are recommended for heart rate control in patients with AAS who have contraindications to or intolerance to IV beta-adrenergic blockers.1336
Diltiazem has been used in the management of anal fissures†.1331, 1332, 1333, 1334 Experts from the American Society of Colon and Rectal Surgeons (ASCRS) and the American College of Gastroenterology (ACG) recommend first-line drug therapy with topical calcium-channel blocking agents (e.g., nifedipine, diltiazem) or topical nitrates (e.g., nitroglycerin rectal ointment) for the treatment of chronic anal fissure that does not respond to initial treatment with dietary fiber supplementation and sitz baths.1331, 1332 Topical nifedipine 0.2-0.5% and topical diltiazem 2% preparations are recommended, but are not commercially available in the US.1331, 1332, 1333 Oral calcium channel blockers (e.g., nifedipine, diltiazem) have also been compared with topical calcium channel blockers in a small number of patients; the ASCRS guidelines state that although rates of healing and pain relief may be similar, topical calcium channel blocker therapy is preferred due to the lower incidence of systemic effects.1332, 1334
Dispensing and Administration Precautions
Diltiazem hydrochloride is administered by direct IV injection, continuous IV infusion, or orally.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703, 706
Diltiazem hydrochloride is administered orally as conventional (immediate-release) tablets, extended-release capsules, and extended-release tablets.100, 187, 274, 323, 324, 325, 600, 601, 603, 703, 705 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.100, 187, 274, 323, 324, 325, 600, 601, 603, 703
Administer conventional tablets orally 3-4 times daily before meals and at bedtime.100 Tablets may be swallowed whole, crushed, or chewed.100 Do not split 30 mg tablets.100 Store at 25°C (excursions permitted to 15-30°C); avoid excessive humidity.100
Diltiazem hydrochloride extended-release capsules (twice-a-day): Administer capsules orally twice daily.603 Store at 20-25°C in a tight, light-resistant container; avoid excessive humidity.603
Diltiazem hydrochloride extended-release capsules (Cardizem® CD and Cartia XT® extended-release capsules): Administer capsules orally once daily.187, 325 Store Cardizem® CD at 25°C (excursions permitted to 15-30°C); avoid excessive humidity.187 Store Cartia XT® at 20-25°C; avoid excessive humidity.325
Diltiazem hydrochloride extended-release capsules (Tiazac® and Tiadylt® ER): Administer capsules orally once daily.274, 601 Alternatively, the preparation may be opened and the entire contents sprinkled on a small amount of applesauce (not hot) immediately prior to administration; subdividing the contents of capsules is not recommended.274, 601 Swallow the entire mixture without chewing.274, 601 Immediately drink a glass of cool water to ensure that all of the mixture is swallowed.274, 601 Do not store the sprinkle/food mixture for use at a later time.274, 601 Store Tiazac® and Tiadylt® ER capsules at 25°C (excursions permitted to 15-30°C); avoid excessive humidity.274, 601
Diltiazem hydrochloride extended-release capsules (Dilt-XR® ): Administer capsules orally once daily; the manufacturer recommends administration in the morning on an empty stomach.324 Capsules should be swallowed whole and not opened, chewed or crushed.324 Store at 20-25°C (excursions permitted to 15-30°C) in a tight, light-resistant container.324
Diltiazem hydrochloride extended-release tablets (Cardizem® LA and Matzim® LA): Administer tablets orally once daily, at approximately the same time, without regard to meals.323, 600 Tablet should be swallowed whole and not chewed or crushed.323, 600 Store at 20-25°C (excursions permitted to 15-30°C); avoid excessive humidity and temperatures above 30°C.323, 600 Dispense in a tight, light-resistant container.323, 600
Diltiazem hydrochloride is administered by direct IV injection or continuous IV infusion in the management of supraventricular tachyarrhythmias.332, 703, 706
For direct IV injection or continuous IV infusion, diltiazem is given slowly under continuous ECG and blood pressure monitoring during the administration period.332, 703, 706 Solutions of the drug should be inspected visually for particulate matter or discoloration prior to IV administration whenever solution and container permit.332, 703, 706
IV injection:When administered by direct IV injection, diltiazem hydrochloride injection containing 5 mg/mL requires no further dilution. 332, 703 Rate of administration is over 2 minutes.332, 703
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.332, 703 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 and 100 mL of 0.9% sodium chloride or 5% dextrose injection.332 A ready-to-use premixed solution of diltiazem in 0.72% sodium chloride injection also is also commercially available in 1 mg/mL concentrations.706 The initial rate of administration is 5 or 10 mg/hour; the rate is adjusted in increments of 5 mg/hour according to response up to a maximum of 15 mg/hour.332, 703, 706
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
Patient Population | Concentration Standards | Dosing Units |
|---|---|---|
Adults | 1 mg/mL | mg/hour |
Dosage of diltiazem hydrochloride preparations is expressed in terms of the hydrochloride salt.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703
For the management of angina due to coronary artery spasm (e.g., Prinzmetal variant angina) or chronic stable angina, the usual initial adult oral dosage of diltiazem hydrochloride 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.100 The average optimum adult oral dosage range for diltiazem hydrochloride tablets appears to be 180-360 mg daily given in 3 or 4 divided doses.100
When diltiazem hydrochloride is administered orally as extended-release capsules (Tiazac®, Dilt-XR®, Tiadylt® ER)274, 324 or extended-release tablets (Cardizem® LA, Matzim® LA)323, 600 for the management of chronic stable angina, the usual initial adult dosage is 120 mg (Dilt-XR®), 120-180 mg (Tiazac®, Tiadylt® ER ) or 180 mg (Cardizem® LA, Matzim® LA) once daily.274, 323, 325, 600, 601 When diltiazem hydrochloride is administered orally as Cardizem® CD or Cartia XT® extended-release capsules for the management of chronic stable angina and angina secondary to coronary artery spasm, the usual initial adult dosage is 120-180 mg once daily.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, 600, 601 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®, Tiadylt® ER,) once daily.187, 274, 323, 324, 325, 600, 601 The manufacturers of Cardizem® CD or Cartia XT® extended-release capsules also state that there is limited clinical experience with diltiazem hydrochloride 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, 325
The manufacturers of Cardizem® CD, Cartia XT®, Dilt-XR® extended-release capsules or Cardizem® LA or Matzim® LA extended-release tablets state that patients adequately controlled with diltiazem therapy alone or in combination with other medications may be switched to Cardizem® CD, Cartia XT®, Cardizem® LA, Dilt-XR®, or Matzim® LA at the nearest equivalent total daily dosage.187, 274, 323, 324, 325, 600 Monitor patients closely; subsequent titration to a higher or lower dosage may be necessary depending on the clinical response of the patient.187, 323, 324, 325, 600, 703
For the management of hypertension in adults receiving diltiazem hydrochloride as monotherapy, the usual initial, maintenance, and maximum dosages of the various oral preparations are described in Table 2.100, 187, 274, 323, 324, 325, 600, 603
Extended-release Preparation | Initial Dosage When Used as Monotherapy | Usual Maintenance Dosage | Maximum Dose |
|---|---|---|---|
Cardizem® CD | 180-240 mg once daily (some patients may respond to lower doses)187 | 240-360 mg/day187 | 480 mg187 |
Cardizem® LA | 180-240 mg once daily323 | 540 mg323 | |
Cartia XT® | 180-240 mg once daily (some patients may respond to lower doses)325 | 240-360 mg/day325 | 480 mg325 |
Diltiazem extended-release capsules (12 hours) | 60-120 mg twice daily603 | 240-360 mg/day603 | |
Dilt-XR® | 180-240 mg once daily (some patients may respond to lower doses)324 | 180-480 mg/day324 | 540 mg324 |
Matzim® LA | 180-240 mg once daily (some patients may respond to lower doses)600 | 540 mg600 | |
Tiazac® and Tiadylt® ER |
Adjust diltiazem dosage by titrating to antihypertensive effect and individual patient needs.100, 187, 274, 323, 324, 325, 600, 601, 603 The maximum hypotensive effect associated with a given dosage level usually is observed within 14 days; therefore, schedule dosage adjustments accordingly.187, 274, 323, 325, 600, 601, 603 Although the usual maintenance dosages vary based upon manufacturer recommendations, 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 state that patients adequately controlled with previous or other diltiazem products may be switched to their diltiazem product at the nearest equivalent daily dosage.187, 323, 324, 325, 600 Monitor patients closely; subsequent titration to a higher or lower dosage may be necessary depending on the clinical response of the patient.187, 323, 324, 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 hydrochloride 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, 325
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, Wolff-Parkinson-White [WPW] syndrome, short PR syndrome), if the rhythm is unresponsive to (i.e., not controlled or converted by) vagal maneuvers or such maneuvers are otherwise contraindicated, 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 the duration of action may be shorter and clinical experience with this dose is limited.256, 332, 700, 703 If the response is inadequate (i.e., conversion to normal sinus rhythm does not occur), 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, 332, 703, 706 Subsequent doses should be individualized for each patient.332, 703, 706 Patients with low body weights should also be dosed on a mg/kg basis.332, 703 The usual adult IV maintenance infusion dose of diltiazem hydrochloride is 5-15 mg/hour.332, 700, 703, 706
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;332, 703 some patients may respond to an initial dose of 0.15 mg/kg, but clinical experience with this dose is limited.332, 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, 332, 703 Subsequent doses should be individualized for each patient.332, 703 A fixed-dose strategy of diltiazem hydrochloride 10 mg administered by direct IV injection† has been an effective initial dose in patients with atrial fibrillation with rapid ventricular response in retrospective trials conducted in the emergency department.1314 For continued reduction of ventricular rate in patients with atrial flutter or fibrillation who have responded to initial therapy with an IV diltiazem hydrochloride loading dose (1 or 2), the recommended initial maintenance infusion rate is 5 or 10 mg/hour (some patients may maintain response to an initial rate of 5 mg/hour); the infusion should begin immediately following the direct IV injection.332, 703, 706 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.332, 703, 706 The safety and efficacy of maintenance infusion rates exceeding 15 mg/hour or for infusions longer than 24 hours have not been established, and use of such dosages is not recommended by the manufacturers.332, 703, 706 The manufacturers state transitioning to other antiarrhythmic agents following IV diltiazem is generally safe, but the prescribing information of the other agent(s) must be considered.332, 703 In controlled clinical trials of alternative antiarrhythmic therapy (e.g., IV or oral digoxin, quinidine, procainamide, oral calcium-channel blockers, oral beta-adrenergic blockers), transference of therapy generally occurred within 3 hours of administration of direct IV injection of diltiazem.332, 703 Clinical experience with transferring therapy following maintenance infusion of diltiazem hydrochloride is limited.332, 703 In determining the appropriateness of transferring therapy, characteristics and dosing guidelines for the alternative drug must be considered.332, 703 For ongoing drug therapy for SVT, some experts recommend an initial oral diltiazem hydrochloride dose of 120 mg and a maximum of 360 mg as daily in divided (conventional tablets) doses or as a single oral dose with a long-acting preparation.700
The manufacturer of Cardizem® conventional tablets state that data are not available concerning dosage requirements in patients with impaired hepatic function.100 In patients with mild-moderate hepatic impairment, the manufacturers of Cardizem® LA and Matzim® LA state that dosage adjustment is unlikely to be needed.332, 600
The manufacturer of Cardizem® conventional tablets state that data are not available concerning dosage requirements in patients with impaired renal function.100 In patients with renal impairment, the manufacturers of Cardizem® LA and Matzim® LA state that dosage adjustment of diltiazem is unlikely to be needed.323, 600
In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
The manufacturer of Dilt-XR® states that patients ≥60 years of age may respond to an initial diltiazem hydrochloride dosage of 120 mg once daily for the treatment of hypertension.324
In patients with low body weight, diltiazem by direct IV injection for the treatment of supraventricular arrhythmia should be dosed on a mg/kg (actual body weight) basis.332, 703
Cardiac Conduction Abnormalities
Diltiazem prolongs AV node refractory periods without significantly prolonging sinus node recovery time, except in patients with sick sinus syndrome.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703 This effect may rarely (<0.5%) result in abnormally slow heart rates (particularly in patients with sick sinus syndrome) or second- or third-degree AV block.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 The manufacturers warn that diltiazem rarely may cause second- or third-degree AV block when the drug is administered IV in the treatment of atrial fibrillation/flutter (rapid ventricular rate control) or in the rapid conversion of paroxysmal supraventricular tachycardia to sinus rhythm.323, 703 If high-degree AV block occurs in patients with sinus rhythm, IV diltiazem should be discontinued and appropriate supportive measures instituted.323, 703 Concomitant use of diltiazem with drugs known to affect cardiac conduction (e.g., beta-adrenergic blockers, digitalis) may result in additive effects on cardiac conduction.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 A patient with Prinzmetal angina developed periods of asystole (2-5 seconds) after a single dose of 60 mg of diltiazem hydrochloride.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Monitor patients for the effect of diltiazem on heart rate and cardiac conduction.323, 600
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.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703
Experience with the use of diltiazem alone or in combination with beta-adrenergic blockers in patients with impaired ventricular function is very limited.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Worsening of congestive heart failure has been reported in patients with preexisting impairment of ventricular function.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Diltiazem should be used cautiously in such patients.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Symptomatic hypotension has been reported in 3.2% of patients receiving IV diltiazem and may also occur occasionally in patients receiving the drug orally.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703 IV diltiazem should be used with caution in hemodynamically compromised patients or in patients taking other drugs that decrease peripheral resistance, intravascular volume, myocardial contractility, or conduction.323, 703
Mild to marked elevations in liver function test results (e.g., AST, ALT, LDH, creatine kinase [CK], creatine phosphokinase [CPK], alkaline phosphatase, bilirubin) and other signs consistent with acute hepatic 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 instances, it is likely in some cases.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703 Mild elevations usually were transient and frequently resolved despite continued oral diltiazem therapy. 100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Elevations in liver function indices consistent with acute hepatic injury following oral diltiazem suggest the potential exists for such an occurrence following administration of IV diltiazem.323, 703 Adverse hepatic effects of oral diltiazem have been reversible following discontinuance of the drug.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Adverse dermatologic effects associated with oral diltiazem may be transient and resolve despite continued therapy with the drug; however, the possibility that diltiazem-induced skin eruptions may progress to erythema multiforme, toxic epidermal necrolysis, Stevens-Johnson syndrome, and/or exfoliative dermatitis should be considered.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703 While these dermatologic effects have not yet been reported with IV diltiazem, they potentially could occur with such administration.323, 703 Discontinue diltiazem if a dermatologic effect persists.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Ventricular premature beats (VPBs) may be present following IV diltiazem administration as well as during cardioversion, other pharmacologic therapy, and during spontaneous conversion of paroxysmal supraventricular tachycardia (PSVT) to sinus rhythm.332, 703 When present on conversion of PSVT to sinus rhythm following IV diltiazem these VPBs are transient, typically considered to be benign, and appear to have no clinical significance.332, 703
The manufacturer of diltiazem hydrochloride extended-release capsules (Dilt-XR®) states that although the drug is contained in a slowly disintegrating matrix, such capsules should be used with caution in patients with preexisting severe GI narrowing (pathologic or iatrogenic).324 However, there have been no reports of obstructive symptoms in patients with known strictures in association with the ingestion of Dilt-XR®.324
Diltiazem has produced embryocidal and fetocidal effects; skeletal, heart, retina, and tongue abnormalities; reductions in early individual pup weights and survival rates during reproduction studies in mice, rats, and rabbits when given in dosages 4-10 times the usual human daily dosa and increases in stillbirths at dosages 20 times or more the usual human dosage.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703 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, 187, 274, 323, 324, 325, 332, 600, 603, 703
Diltiazem is distributed into milk.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703 One report suggests concentrations in breast milk may approximate serum levels;100, 187, 274, 323, 324, 325, 332, 600, 603, 703 there is potential for serious adverse reactions in nursing infants from diltiazem.323, 600 The manufacturers state that an alternative method of infant feeding should be used if diltiazem therapy is considered necessary in nursing women;100, 187, 274, 323, 324, 325, 332, 600, 603, 703 the importance of the drug to the mother should be considered in this decision.323, 600
Females and Males of Reproductive Potential
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, 274, 323, 324, 325, 332, 600, 601, 603, 703
Safety and efficacy of diltiazem in pediatric patients have not been established.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703
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, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703 The manufacturers of diltiazem state that dosage for geriatric patients should be selected carefully usually starting at the low end of the dosage range, reflecting the greater frequency of decreased hepatic, renal, and/or cardiac function and of concomitant disease and drug therapy.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Diltiazem is metabolized extensively by the liver and excreted in urine and bile.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703 Diltiazem should be used with caution in patients with hepatic impairment; significant liver enzyme elevations consistent with acute hepatic injury have been reported rarely.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 In a study conducted with immediate-release diltiazem, an increased half-life and a 69% increase in AUC was observed in hepatically impaired patients with cirrhosis compared with patients having normal hepatic function.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 The manufacturers make no specific recommendations for dosage adjustment in patients with impaired hepatic function;100 however, no dosage adjustment is likely to be needed in those with mild to moderate hepatic impairment.323, 600
Diltiazem is metabolized extensively by the liver and excreted in urine and bile.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Some evidence suggests that the pharmacokinetic profile after oral administration does not differ significantly in patients with severely impaired renal function compared with those having normal renal function.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 No dosage adjustment is necessary in patients with impaired renal function 332, 703
Oral Preparations: The most common adverse effects reported in clinical trials for the treatment of hypertension and angina are peripheral edema, headache, nausea or dyspepsia, dizziness, fatigue, bradycardia, first-degree AV block, cough, rash, asthenia, dyspnea, and flushing.100, 187, 274, 323, 324, 325, 600, 601, 603
IV Preparations: The most common adverse effects reported in clinical trials for the acute treatment of atrial fibrillation/flutter or paroxysmal supraventricular tachycardia are hypotension; injection site reactions (e.g., itching, burning), vasodilation (flushing), and arrhythmia (junctional rhythm or isorhythmic dissociation).332, 703
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, 274, 323, 324, 325, 332, 600, 601, 603, 703
Diltiazem is a substrate of the cytochrome P-450 (CYP) isoenzyme 3A4.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703
Diltiazem also inhibits CYP3A4.100, 187, 274, 323, 324, 325, 332, 600, 601, 603, 703
Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes
Diltiazem is a substrate and inhibitor of CY3A4.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 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, 187, 274, 323, 324, 325, 332, 600, 603, 703 Diltiazem may competitively inhibit CYP3A4-dependent metabolism of other drugs, potentially altering oral bioavailability and/or clearance of these drugs.100, 116, 187, 274, 323, 324, 325, 332, 600, 603, 703 Diltiazem has been shown to inhibit metabolism of aminopyrine in vitro, and the drug has substantially reduced antipyrine clearance via apparent inhibition of oxidative metabolism in healthy adults.116, 133 Dosages 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 (e.g., cyclosporine) or in patients with renal and/or hepatic impairment.100, 116, 133, 187, 274, 323, 324, 325, 332, 600, 603, 703
There are conflicting reports on whether diltiazem substantially affects the pharmacokinetics of digoxin when the drugs are administered concomitantly.100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110 In some studies, diltiazem reportedly increased average steady-state serum digoxin concentrations by about 20-50%,100, 102, 105, 107, 108, 187, 274, 323, 324, 325, 600, 603 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.100, 103, 106, 109, 110, 187, 274, 323, 324, 325, 600, 603 Since there are conflicting reports, the manufacturers recommend that serum digoxin concentrations should be monitored when initiating, adjusting, and discontinuing diltiazem therapy to avoid possible over- or under-digitalization.100, 187, 274, 323, 324, 325, 332, 600, 603 Digoxin does not appear to affect the protein binding of diltiazem.100, 103, 104, 105, 274, 323, 324, 325, 600, 603 Concomitant use of diltiazem and a cardiac glycoside may result in an additive effect on AV nodal conduction.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 The manufacturers state that IV diltiazem has been administered to patients receiving either IV or oral digitalis therapy and such combination was well tolerated without serious adverse effects.332, 703 Monitor patients for excessive slowing of the heart rate and/or AV block if diltiazem and digoxin are used concomitantly.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
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.323, 600
BetaBeta-Adrenergic Blocking Agents
Concomitant use of diltiazem with beta-adrenergic blockers can have additive negative effects on myocardial contractility, heart rate, and AV conduction.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 The manufacturer states that controlled and uncontrolled studies suggest that concomitant use of diltiazem and beta-adrenergic blockers is usually well tolerated; however, insufficient data are available to predict the effects of concomitant treatment, particularly in patients with left ventricular dysfunction or cardiac conduction abnormalities100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Diltiazem has been administered IV to patients maintained on oral beta-adrenergic blockers, and the combination generally is well tolerated.703 However, the possibility of bradycardia, AV block, and/or depression of contractility with such concomitant therapy should be considered.703 Administration of IV diltiazem and IV beta-adrenergic blockers within a few hours of each other is contraindicated.332, 703 When diltiazem was administered concomitantly with propranolol in 5 healthy individuals, propranolol blood levels increased in all subjects and AUC increased approximately 50%.100, 187, 274, 324, 325, 332, 600, 603 In vitro, propranolol appears to be displaced from its binding sites by diltiazem.100, 187, 274, 323, 324, 325, 600, 603 Propranolol dosage adjustment may be necessary when concomitant diltiazem therapy is initiated or discontinued.100, 187, 274, 323, 324, 325, 332, 600, 603 Propranolol does not appear to affect the protein binding of diltiazem.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
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.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 When used concomitantly, anesthetics and calcium-channel blockers should be titrated carefully.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Concomitant use of diltiazem and ivabradine increases the systemic exposure of ivabradine and may exacerbate bradycardia and conduction disturbances.100, 187, 274, 323, 324, 325, 332, 600, 603 Concomitant use of ivabradine and diltiazem should be avoided.100, 187, 274, 323, 324, 325, 332, 600, 603
In vitro data shows that alcohol increases the rate at which diltiazem is released from certain preparations (Cardizem CD®, Cartia XT®).187, 325 This may lead to more rapid diltiazem absorption, increased systemic exposure, and associated dose-related adverse reactions.187, 325 The manufacturers of such preparations suggest patients avoid consumption of alcohol.187, 325
Diltiazem appears to inhibit the CYP3A4 isoenzyme responsible for metabolism of midazolam and triazolam.1310 Concomitant use of diltiazem with midazolam or triazolam increased AUC, peak plasma concentrations, and elimination half-lives of these benzodiazepines by about 300-400, 200, and 150-250%, respectively (compared with placebo), in clinical studies.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Concomitant use with diltiazem may result in increased adverse benzodiazepine effects (e.g., prolonged sedation, respiratory depression).100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Concomitant use of diltiazem with buspirone increased the AUC and peak plasma concentration of buspirone by about 550 and 410%, respectively in a placebo-controlled clinical study.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 The elimination half-life and time to peak plasma concentration of buspirone were not affected by diltiazem.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 This interaction may result in enhanced effects and increased adverse reactions associated with buspirone.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 In patients receiving buspirone concomitantly with diltiazem, dosage adjustment of buspirone may be necessary and should be based on clinical assessment.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Concomitant use of oral diltiazem and carbamazepine can result in increased carbamazepine concentrations and subsequent toxicity; carbamazepine concentrations may increase by 40-72%.100, 187, 201, 202, 204, 205, 206, 207, 274, 323, 324, 325, 332, 600, 603, 703 It has been suggested that diltiazem may inhibit hepatic metabolism of carbamazepine via CYP3A4.201, 202, 204, 205, 206, 207, 1310 Monitor patients receiving concomitant diltiazem and carbamazepine for signs and symptoms of carbamazepine toxicity (e.g., drowsiness, dizziness, nausea, vomiting, seizures).100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in patients receiving diltiazem and clonidine concomitantly.100, 187, 274, 323, 324, 325, 332, 600, 603 Patients receiving such concomitant therapy should have their heart rate monitored.100, 187, 274, 323, 324, 325, 332, 600, 603
A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 In such patients, a cyclosporine dose reduction ranging from 15-48% was necessary to maintain trough concentrations similar to those seen prior to the addition of diltiazem.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 It has been suggested that diltiazem may interfere with metabolism of cyclosporine via CYP3A4 inhibition.1310 Concomitant administration of cyclosporine with diltiazem (especially when diltiazem therapy is initiated, adjusted, or discontinued) requires cyclosporine concentration monitoring.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated. 100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Concomitant administration of diltiazem and efavirenz, a CYP3A4 inducer, decreased diltiazem AUC 69%.1312 Experts recommend diltiazem dosage titration based on clinical response.1312
Decreased diltiazem concentrations are possible when administered with etravirine, a CYP3A4 inducer.1312 Experts recommend diltiazem dosage titration based on clinical response.1312
Cimetidine, a cytochrome P-450 inhibitor, can increase plasma diltiazem concentrations.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Peak plasma diltiazem concentrations were increased by approximately 58% and area under the plasma concentration-time curve by 53% 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, 187, 274, 323, 324, 325, 332, 600, 603, 703 Concomitant administration of ranitidine produced minor, nonsignificant alterations in the pharmacokinetic parameters of diltiazem.100, 125, 187, 274, 323, 324, 325, 332, 600, 603, 703 Cimetidine and ranitidine increased peak plasma deacetyldiltiazem concentrations by about 65 and 60%, respectively.125 Monitor patients currently receiving diltiazem therapy for a change in pharmacologic effect when initiating and discontinuing therapy with cimetidine; dosage adjustment of diltiazem may be necessary.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Atazanavir: Concomitant use of diltiazem and atazanavir may result in increased plasma concentrations and AUC (125%) of diltiazem and an additive effect on PR interval prolongation.318, 1312 A greater AUC increase is likely when diltiazem is combined with cobicistat- or ritonavir-boosted atazanavir.318, 1312 Caution is advised if diltiazem and atazanavir are used concomitantly; a 50% reduction in diltiazem hydrochloride dosage and ECG monitoring also are recommended.318, 1312 When diltiazem is initiated in the those already taking atazanavir or cobicistat- or ritonavir-boosted atazanavir, experts recommend initiating diltiazem with the lowest dose and titrating to clinical response and adverse events.1312
Darunavir: Increased diltiazem AUC is possible when used concomitantly with cobicistat- or ritonavir-boosted darunavir.1312 Experts recommend titrating the diltiazem dose according to clinical response and adverse events.1312
Concomitant use of diltiazem and HMG-CoA reductase inhibitors metabolized by CYP3A4 (e.g., lovastatin, simvastatin) can increase statin exposure and the risk of myopathy, including rhabdomyolysis. 100, 187, 274, 323, 324, 325, 332, 600, 603, 703, 1310 When a statin is required in a patient receiving diltiazem, a non-CYP3A4-metabolized statin should be used if possible, although experts state these combination therapies may be considered in appropriate patients when the potential for benefits outweighs potential risks. 100, 187, 274, 323, 324, 325, 332, 600, 603, 1311
Atorvastatin: Concomitant administration of diltiazem with atorvastatin may result in a 51% increase in atorvastatin exposure.1311 A single case of rhabdomyolysis has been reported when diltiazem was initiated in a patient with atrial fibrillation on stable treatment with atorvastatin.1310, 1311 Based on this limited information, experts state concomitant diltiazem and atorvastatin use results in a minor increase in statin exposure and such combination therapy is reasonable.1311
Lovastatin: Administration of sustained-release diltiazem 120 mg twice daily for 2 weeks followed by a single dose of lovastatin 20 mg increased the mean AUC and peak plasma concentration of lovastatin by 3- to 4-fold compared with lovastatin alone in a 10-subject randomized crossover study.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Diltiazem plasma levels were not significantly affected by lovastatin.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 If used concomitantly with diltiazem, the manufacturer recommends initiating lovastatin at 10 mg daily and dosage should not exceed 20 mg daily.602 Patients receiving lovastatin concomitantly with diltiazem should be monitored for signs and symptoms of any statin-related adverse events.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Pravastatin: No significant change in pravastatin mean AUC and peak plasma concentration occurred when a single dose of pravastatin 20 mg was administered following 2 weeks of sustained-release diltiazem 120 mg twice daily in a 10-subject randomized crossover study.100, 187, 274, 323, 324, 325, 332, 600, 603
Simvastatin: Concomitant 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 5-fold increase in mean simvastatin AUC in a limited number of healthy individuals.100, 187, 274, 323, 324, 325, 332, 600, 603 Based on computer simulations using these data, administration of diltiazem 480 mg once daily may be expected to result in an 8- to 9-fold increase in mean simvastatin AUC.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 If diltiazem is used concomitantly with simvastatin, the manufacturer states that daily dosages should not exceed 240 and 10 mg, respectively.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Patients receiving simvastatin concomitantly with diltiazem should be monitored for evidence of simvastatin toxicity (e.g., rhabdomyolysis, myositis).100, 187, 274, 323, 324, 325, 332, 600, 603, 703
The manufacturers of diltiazem state that sublingual nitroglycerin may be administered as required during diltiazem therapy for relief of acute angina.100, 187, 274, 323, 324, 325 The manufacturers also state that concomitant prophylactic therapy with short- or long-acting nitrates may be administered safely during diltiazem therapy,100, 187, 274, 324, 325 but that controlled studies to evaluate concomitant use of the drugs have not been performed.100
Concomitant use of diltiazem with quinidine increases the AUC and elimination half-life of quinidine by 51 and 36%, respectively, and decreases quinidine oral clearance by 33%.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Patients receiving quinidine concomitantly with diltiazem should be monitored for evidence of quinidine toxicity (e.g., changes in vision, dizziness, lightheadedness, irregular heartbeat) and quinidine dosage should be adjusted as necessary.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
Concomitant use of rifampin with diltiazem lowered the plasma diltiazem concentrations to undetectable levels.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 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, 187, 274, 323, 324, 325, 332, 600, 603, 703
Diltiazem is a nondihydropyridine benzothiazepine-derivative calcium-channel blocker.100, 187, 274, 323, 324, 325, 600, 601, 603, 703, 1310, 1310 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.100, 332 Diltiazem is a peripheral arterial vasodilator; the drug acts directly on vascular smooth muscle causing reduction in peripheral vascular resistance (afterload) and blood pressure.100, 332 Diltiazem exerts substantial inhibitory effects on the cardiac conduction system, acting principally at the atrioventricular (AV) node to slow conduction time and prolong AV nodal refractoriness.332
Diltiazem hydrochloride is well absorbed from the GI tract following oral administration of the conventional tablets.100 Following single oral doses of the conventional tablets, detectable and peak plasma levels occur within 30-60 minutes and 2-4 hours, respectively, after administration.100 Following a single 120-mg dose of the extended-release capsules, detectable and peak plasma levels occur within 2-3 and 6-11 hours, respectively.603 Following a single 360-mg dose of Cardizem® CD or Cartia XT® extended-release capsules, detectable plasma and peak plasma levels occur within 2 and 10-14 hours, respectively; absorption occurs throughout the dosing interval.187, 325 Following a single 360-mg dose of Cardizem® LA and Matzim® LA extended-release tablets, detectable and peak plasma levels occur within 3-4 and 11-18 hours, respectively.323, 600 The oral bioavailability of diltiazem from extended-release capsules at steady state is more than 93% when compared with that of the conventional tablets.187, 274, 325, 601 The absolute bioavailability of diltiazem from a single dose of Dilt-XR®, compared with IV administration, is approximately 40%.100, 324 Only about 40% of an oral dose of diltiazem reaches systemic circulation as unchanged drug since diltiazem undergoes extensive metabolism on first pass through the liver.100 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 Food does not appear to affect the extent of absorption, but rate of absorption may be increased if some extended-release preparations are taken with a high-fat meal.187, 274, 323, 324, 325, 601 About 70-80% of diltiazem is bound to plasma proteins; approximately 30% is bound to albumin while other constituents bind the remainder.100, 332 Diltiazem has a large volume of distribution because of its lipophilicity and is rapidly and extensively distributed into body tissues.191, 259 Diltiazem is distributed into breast milk, apparently in concentrations approximately equal to maternal serum concentrations.100, 101, 332 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. 132, 134, 135, 136, 137, 182, 183, 241, 242 About 10-20% of diltiazem is metabolized to deacetyldiltiazem, which is 25-50% as potent as a coronary vasodilator when compared with diltiazem, the parent compound.100 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 The plasma elimination half-life following single or multiple drug administration of diltiazem conventional tablets is approximately 3-4.5 hours.100 The apparent elimination half-life after single or multiple dosing of Tiazac® extended-release capsules is 4-9.5 hours (mean 6.5 hours).274 The apparent elimination half-life after single or multiple dosing of Cardizem® CD and Cartia XT® extended-release capsules is 5-8 hours.187, 325 Each extended-release diltiazem hydrochloride capsule (Dilt-XR®) consists of multiple 60-mg tablets contained in a slowly disintegrating matrix that slowly releases the drug over approximately 24 hours throughout the GI tract.324 Controlled absorption of diltiazem begins within 1 hour, with maximum plasma concentrations within 4-6 hours of administration.324 The apparent steady-state half-life of diltiazem following once daily administration of Dilt-XR® is 5-10 hours; this prolongation is attributed to continued absorption of diltiazem rather than to alterations in its elimination.324 The apparent elimination half-life after single or multiple dosing of Cardizem® LA and Matzim® LA extended-release tablets is 6-9 hours.323, 600 Plasma half-life of diltiazem may be increased in geriatric patients.191, 239 Liver cirrhosis has been shown to increase diltiazem's apparent AUC and to prolong its half-life.100, 187, 274, 323, 324, 325, 332, 600, 603, 703 Some evidence suggests that the pharmacokinetic profile of the oral drug does not differ significantly in patients with severely impaired renal function compared with those patients having normal renal function.135 Diltiazem does not appear to be eliminated by hemodialysis or peritoneal dialysis.100, 274, 323, 325, 332, 600 Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdosage.100, 187, 274, 323, 325, 332, 600 Approximately 2-4% of a dose of the drug is excreted in urine unchanged.100, 135, 259, 332 The remainder of the drug is eliminated in urine and via bile, mainly as metabolites.100, 187, 274, 323, 324, 325, 332, 600, 603, 703
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.247, 252, 332, 703 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.246, 247, 252, 332, 703 Blood pressure reductions following direct IV injection of diltiazem, if they occur, generally are short-lived but may last 1-3 hours.332, 703 In patients with paroxysmal supraventricular tachycardia (PSVT) conversion to normal sinus rhythm usually occurs within 3 minutes of the first or second direct IV injections of diltiazem hydrochloride.332, 703 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 (mean duration 7 hours) postinfusion.242, 332, 703 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, 239, 332, 703 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, 239, 332, 703 Following single diltiazem doses administered via direct IV injection, plasma concentrations of the principal metabolites, deacetyldiltiazem and N-monodesmethyldiltiazem, are initially low or undetectable; however, detectable plasma concentrations of active metabolites are observed following 24 hour constant rate intravenous infusion.239, 241, 242, 332, 703 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.332, 703 Constant rate diltiazem IV infusions at 3, 5, 7, and 11 mg/h are predicted to produce steady-state plasma diltiazem concentrations equivalent to 120-, 180-, 240-,and 360-mg total daily oral doses of diltiazem tablets or diltiazem hydrochloride extended-release capsules based on the results of pharmacokinetic studies in healthy volunteers administered different oral diltiazem hydrochloride formulations.332, 703
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.
Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.
Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Oral | Capsules, extended-release | 60 mg* | DilTIAZem Hydrochloride Capsules Extended-release (12 hours) | |
90 mg* | DilTIAZem Hydrochloride Capsules Extended-release (12 hours) | |||
120 mg* | Cardizem® CD (24 hours) | Bausch | ||
Cartia XT® (24 hours) | Teva | |||
Dilt-XR® (24 hours) | ||||
DilTIAZem Hydrochloride Capsules Extended-release (12 hours) | ||||
DiltTIAZem Hydrochloride Capsules Extended-release (24 hours) | ||||
Tiadylt® ER (24 hours) | Zydus | |||
Tiazac® (24 hours) | Bausch | |||
180 mg* | Cardizem® CD (24 hours) | Bausch | ||
Cartia XT® (24 hours) | Teva | |||
Dilt-XR® (24 hours) | Apotex | |||
DilTIAZem Hydrochloride Capsules Extended-release (24 hours) | ||||
Tiadylt® ER (24 hours) | Zydus | |||
Tiazac® (24 hours) | Bausch | |||
240 mg* | Cardizem® CD (24 hours) | Bausch | ||
Cartia XT® (24 hours) | Teva | |||
Dilt-XR® (24 hours) | Apotex | |||
DilTIAZem Hydrochloride Capsules Extended-release (24 hours) | ||||
Tiadylt® ER (24 hours) | Zydus | |||
Tiazac® (24 hours) | Bausch | |||
300 mg* | Cardizem® CD (24 hours) | Bausch | ||
Cartia XT® (24 hours) | Teva | |||
DilTIAZem Hydrochloride Capsules Extended-release (24 hours) | ||||
Tiadylt® ER (24 hours) | Zydus | |||
Tiazac® (24 hours) | Bausch | |||
360 mg* | Cardizem®CD (24 hours) | Bausch | ||
DilTIAZem Hydrochloride Capsules Extended-release (24 hours) | ||||
Tiadylt® ER (24 hours) | Zydus | |||
Tiazac® (24 hours) | ||||
420 mg* | DilTIAZem Hydrochloride Capsules Extended-release (24 hours) | |||
Tiadylt® ER (24 hours) | Zydus | |||
Tiazac® (24 hours) | Bausch | |||
Tablets | 30 mg* | Cardizem® | Bausch | |
60 mg* | Cardizem® (scored) | Bausch | ||
DilTIAZem Hydrochloride Tablets | ||||
90 mg* | Cardizem® (scored) | Bausch | ||
DilTIAZem Hydrochloride Tablets | ||||
120 mg* | Cardizem® (scored) | Bausch | ||
DilTIAZem Hydrochloride Tablets | ||||
Tablets, extended-release | 120 mg* | Cardizem® LA (24 hours) | Bausch | |
DilTIAZem Hydrochloride Tablets Extended-release (24 hours) | ||||
180 mg* | Cardizem® LA (24 hours) | Bausch | ||
DilTIAZem Hydrochloride Tablets Extended-release (24 hours) | ||||
Matzim® LA (24 hours) | ||||
240 mg* | Cardizem® LA (24 hours) | Bausch | ||
DilTIAZem Hydrochloride Tablets Extended-release (24 hours) | ||||
Matzim® LA (24 hours) | Actavis | |||
300 mg* | Cardizem® LA (24 hours) | Bausch | ||
DilTIAZem Hydrochloride Tablets Extended-release (24 hours) | ||||
Matzim® LA (24 hours) | Actavis | |||
360 mg* | Cardizem® LA (24 hours) | Bausch | ||
DilTIAZem Hydrochloride Tablets Extended-release (24 hours) | ||||
Matzim® LA (24 hours) | Actavis | |||
420 mg* | Cardizem® LA (24 hours) | Bausch | ||
DilTIAZem Hydrochloride Tablets Extended-release (24 hours) | ||||
Matzim® LA (24 hours) | Actavis | |||
Parenteral | For injection, for IV infusion only | 100 mg* | ||
Injection | 5 mg/mL (25, 50, and 125 mg)* |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Routes | Dosage Forms | Strengths | Brand Names | Manufacturer |
|---|---|---|---|---|
Parenteral | Injection, for IV infusion only | 100 mg/100 mL (1 mg/mL) diltiazem hydrochloride in 0.72% sodium chloride* | DilTIAZem Hydrochloride in Sodium Chloride Injection | |
250 mg/250 mL (1 mg/mL) diltiazem hydrochloride in 0.72% sodium chloride* | DilTIAZem Hydrochloride in Sodium Chloride Injection |
* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name
Only references cited for selected revisions after 1984 are available electronically.
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