Mechanisms of Action

Diltiazem inhibits the influx of calcium (Ca 2+) ions during membrane depolarization of cardiac and vascular smooth muscle. The therapeutic benefits of diltiazem in supraventricular tachycardias are related to its ability to slow AV nodal conduction time and prolong AV nodal refractoriness. Diltiazem exhibits frequency (use) dependent effects on AV nodal conduction such that it may selectively reduce the heart rate during tachycardias involving the AV node with little or no effect on normal AV nodal conduction at normal heart rates.

Diltiazem slows the ventricular rate in patients with a rapid ventricular response during atrial fibrillation or atrial flutter. Diltiazem converts paroxysmal supraventricular tachycardia (PSVT) to normal sinus rhythm by interrupting the reentry circuit in AV nodal reentrant tachycardias and reciprocating tachycardias, e.g., Wolff-Parkinson-White syndrome (WPW).

Diltiazem prolongs the sinus cycle length. It has no effect on the sinus node recovery time or on the sinoatrial conduction time in patients without SA nodal dysfunction. Diltiazem has no significant electrophysiologic effects on tissues in the heart that are fast sodium channel dependent, e.g., His-Purkinje tissue, atrial and ventricular muscle, and extranodal accessory pathways.

Like other calcium channel antagonists, because of its effect on vascular smooth muscle, diltiazem decreases total peripheral resistance resulting in a decrease in both systolic and diastolic blood pressure.

Hemodynamics

In patients with cardiovascular disease, diltiazem hydrochloride administered intravenously in single bolus doses, followed in some cases by a continuous infusion, reduced blood pressure, systemic vascular resistance, the rate-pressure product, and coronary vascular resistance and increased coronary blood flow. In a limited number of studies of patients with compromised myocardium (severe congestive heart failure, acute myocardial infarction, hypertrophic cardiomyopathy), administration of intravenous diltiazem produced no significant effect on contractility, left ventricular end diastolic pressure, or pulmonary capillary wedge pressure. The mean ejection fraction and cardiac output/index remained unchanged or increased. Maximal hemodynamic effects usually occurred within 2 to 5 minutes of an injection. However, in rare instances, worsening of congestive heart failure has been reported in patients with preexisting impaired ventricular function.

Pharmacodynamics

The prolongation of PR interval correlated significantly with plasma diltiazem concentration in normal volunteers using the Sigmoidal Emax model. Changes in heart rate, systolic blood pressure, and diastolic blood pressure did not correlate with diltiazem plasma concentrations in normal volunteers. Reduction in mean arterial pressure correlated linearly with diltiazem plasma concentration in a group of hypertensive patients.

In patients with atrial fibrillation and atrial flutter, a significant correlation was observed between the percent reduction in HR and plasma diltiazem concentration using the Sigmoidal Emax model. Based on this relationship, the mean plasma diltiazem concentration required to produce a 20% decrease in heart rate was determined to be 80 ng/mL. Mean plasma diltiazem concentrations of 130 ng/mL and 300 ng/mL were determined to produce reductions in heart rate of 30% and 40%.

Pharmacokinetics and Metabolism

Following a single intravenous injection in healthy male volunteers, diltiazem hydrochloride appears to obey linear pharmacokinetics over a dose range of 10.5 to 21 mg. The plasma elimination half-life is approximately 3.4 hours. The apparent volume of distribution of diltiazem is approximately 305 L. Diltiazem is extensively metabolized in the liver with a systemic clearance of approximately 65 L/h.

After constant rate intravenous infusion to healthy male volunteers, diltiazem exhibits nonlinear pharmacokinetics over an infusion range of 4.8 to 13.2 mg/h for 24 hours. Over this infusion range, as the dose is increased, systemic clearance decreases from 64 to 48 L/h while the plasma elimination half-life increases from 4.1 to 4.9 hours. The apparent volume of distribution remains unchanged (360 to 391 L). In patients with atrial fibrillation or atrial flutter, diltiazem systemic clearance has been found to be decreased compared to healthy volunteers. In patients administered bolus doses ranging from 2.5 mg to 38.5 mg, systemic clearance averaged 36 L/h. In patients administered continuous infusions at 10 mg/h or 15 mg/h for 24 hours, diltiazem systemic clearance averaged 42 L/h and 31 L/h, respectively.

Based on the results of pharmacokinetic studies in healthy volunteers administered different oral diltiazem hydrochloride formulations, constant rate intravenous infusions of diltiazem hydrochloride 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 hydrochloride tablets or diltiazem hydrochloride extended-release capsules.

After oral administration, diltiazem undergoes extensive metabolism in man by deacetylation, N-demethylation, and O-demethylation via cytochrome P-450 (oxidative metabolism) in addition to conjugation. Metabolites N-monodesmethyldiltiazem, desacetyldiltiazem, desacetyl-N-monodesmethyldiltiazem, desacetyl-O-desmethyldiltiazem, and desacetyl-N, O-desmethyldiltiazem have been identified in human urine. Following oral administration, 2% to 4% of the unchanged diltiazem appears in the urine. Drugs which induce or inhibit hepatic microsomal enzymes may alter diltiazem disposition.

Following single intravenous injection of diltiazem hydrochloride, however, plasma concentrations of N-mono-desmethyldiltiazem and desacetyldiltiazem, two principal metabolites found in plasma after oral administration, are typically not detected. These metabolites are observed, however, following 24 hour constant rate intravenous infusion. Total radioactivity measurement following short IV administration in healthy volunteers suggests the presence of other unidentified metabolites which attain higher concentrations than those of diltiazem and are more slowly eliminated; half-life of total radioactivity is about 20 hours compared to 2 to 5 hours for diltiazem.

Diltiazem hydrochloride is 70% to 80% bound to plasma proteins. In vitro studies suggest alpha1-acid glycoprotein binds approximately 40% of the drug at clinically significant concentrations. Albumin appears to bind approximately 30% of the drug, while other constituents bind the remaining bound fraction. Competitive in vitro ligand binding studies have shown that diltiazem hydrochloride binding is not altered by therapeutic concentrations of digoxin, phenytoin, hydrochlorothiazide, indomethacin, phenylbutazone, propranolol, salicylic acid, tolbutamide, or warfarin.

Renal insufficiency, or even end-stage renal disease, does not appear to influence diltiazem disposition following oral administration. Liver cirrhosis was shown to reduce diltiazem’s apparent oral clearance and prolong its half-life.

Atrial Fibrillation or Atrial Flutter

Temporary control of rapid ventricular rate in atrial fibrillation or atrial flutter. It should not be used in patients with atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in Wolff-Parkinson-White (WPW) syndrome or short PR syndrome.

Paroxysmal Supraventricular Tachycardia

Rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. This includes AV nodal reentrant tachycardias and reciprocating tachycardias associated with an extranodal accessory pathway such as the WPW syndrome or short PR syndrome. Unless otherwise contraindicated, appropriate vagal maneuvers should be attempted prior to administration of diltiazem hydrochloride injection.

The use of diltiazem hydrochloride injection should be undertaken with caution when the patient is compromised hemodynamically or is taking other drugs that decrease any or all of the following: peripheral resistance, myocardial filling, myocardial contractility, or electrical impulse propagation in the myocardium.

For either indication and particularly when employing continuous intravenous infusion, the setting should include continuous monitoring of the ECG and frequent measurement of blood pressure. A defibrillator and emergency equipment should be readily available.

In domestic controlled trials in patients with atrial fibrillation or atrial flutter, bolus administration of diltiazem hydrochloride injection was effective in reducing heart rate by at least 20% in 95% of patients. Diltiazem hydrochloride injection rarely converts atrial fibrillation or atrial flutter to normal sinus rhythm. Following administration of one or two intravenous bolus doses of diltiazem injection, response usually occurs within 3 minutes and maximal heart rate reduction generally occurs in 2 to 7 minutes. Heart rate reduction may last from 1 to 3 hours. If hypotension occurs, it is generally short-lived, but may last from 1 to 3 hours.

A 24-hour continuous infusion of diltiazem injection in the treatment of atrial fibrillation or atrial flutter maintained at least a 20% heart rate reduction during the infusion in 83% of patients. Upon discontinuation of infusion, heart rate reduction may last from 0.5 hours to more than 10 hours (median duration 7 hours). Hypotension, if it occurs, may be similarly persistent.

In the controlled clinical trials, 3.2% of patients required some form of intervention (typically, use of intravenous fluids or the Trendelenburg position) for blood pressure support following diltiazem hydrochloride injection.

In domestic controlled trials, bolus administration of diltiazem hydrochloride injection was effective in converting PSVT to normal sinus rhythm in 88% of patients within 3 minutes of the first or second bolus dose.

Symptoms associated with the arrhythmia were improved in conjunction with decreased heart rate or conversion to normal sinus rhythm following administration of diltiazem hydrochloride injection.

Cardiac Conduction

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

Congestive Heart Failure

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

Hypotension

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

Acute Hepatic Injury

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

Ventricular Premature Beats (VPBs)

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

General

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

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

Drug Interactions

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

Pregnancy

Nursing Mothers

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

Pediatric Use

Safety and effectiveness in pediatric patients have not been established.

Geriatric Use

Clinical studies of diltiazem did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Cardiovascular

Asystole, atrial flutter, AV block first degree, AV block second degree, bradycardia, chest pain, congestive heart failure, sinus pause, sinus node dysfunction, syncope, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia.

Dermatologic

Pruritus, sweating.

Gastrointestinal

Constipation, elevated SGOT or alkaline phosphatase, nausea, vomiting.

Nervous System

Dizziness, paresthesia.

Other

Amblyopia, asthenia, dry mouth, dyspnea, edema, headache, hyperuricemia. Although not observed in clinical trials with diltiazem hydrochloride injection, the following events associated with oral diltiazem may occur.

Bradycardia

Administer atropine (0.6 to 1 mg). If there is no response to vagal blockade administer isoproterenol cautiously.

High-Degree AV Block

Treat as for bradycardia above. Fixed high-degree AV block should be treated with cardiac pacing.

Cardiac Failure

Administer inotropic agents (isoproterenol, dopamine, or dobutamine) and diuretics.

Hypotension

Vasopressors (e.g., dopamine or levarterenol bitartrate).

The effectiveness of intravenous calcium administration to reverse the pharmacological effects of diltiazem overdose has been inconsistent. In a few reported cases, overdose with calcium channel blockers associated with hypotension and bradycardia that was initially refractory to atropine became more responsive to atropine after the patients received intravenous calcium. In some cases intravenous calcium has been administered (1 g calcium chloride or 3 g calcium gluconate) over 5 minutes, and repeated every 10 to 20 minutes as necessary. Calcium gluconate has also been administered as a continuous infusion at a rate of 2 g per hour for 10 hours. Infusions of calcium for 24 hours or more may be required. Patients should be monitored for signs of hypercalcemia.

Actual treatment and dosage should depend on the severity of the clinical situation and the judgment and experience of the treating physician.

Diltiazem does not appear to be removed by peritoneal or hemodialysis. Limited data suggest that plasmapheresis or charcoal hemoperfusion may hasten diltiazem elimination following overdose.

The intravenous LD 50s in mice and rats were 60 and 38 mg/kg, respectively. The toxic dose in man is not known.

Direct Intravenous Single Injections (Bolus)

The initial dose of diltiazem hydrochloride injection should be 0.25 mg/kg actual body weight as a bolus administered over 2 minutes (20 mg is a reasonable dose for the average patient). If response is inadequate, a second dose may be administered after 15 minutes. The second bolus dose of diltiazem hydrochloride injection should be 0.35 mg/kg actual body weight administered over 2 minutes (25 mg is a reasonable dose for the average patient). Subsequent intravenous bolus doses should be individualized for each patient. Patients with low body weights should be dosed on a mg/kg basis. Some patients may respond to an initial dose of 0.15 mg/kg, although duration of action may be shorter. Experience with this dose is limited.

Continuous Intravenous Infusion

For continued reduction of the heart rate (up to 24 hours) in patients with atrial fibrillation or atrial flutter, an intravenous infusion of diltiazem hydrochloride injection may be administered. Immediately following bolus administration of 20 mg (0.25 mg/kg) or 25 mg (0.35 mg/kg) diltiazem hydrochloride injection and reduction of heart rate, begin an intravenous infusion of diltiazem hydrochloride. The recommended initial infusion rate of diltiazem hydrochloride is 10 mg/h. Some patients may maintain response to an initial rate of 5 mg/h. The infusion rate may be increased in 5 mg/h increments up to 15 mg/h as needed, if further reduction in heart rate is required. The infusion may be maintained for up to 24 hours.

Diltiazem shows dose-dependent, non-linear pharmacokinetics. Duration of infusion longer than 24 hours and infusion rates greater than 15 mg/h have not been studied. Therefore, infusion duration exceeding 24 hours and infusion rates exceeding 15 mg/h are not recommended.

Compatibility

Diltiazem hydrochloride injection was tested for compatibility with three commonly used intravenous fluids at a maximal concentration of 1 mg diltiazem hydrochloride per milliliter. Diltiazem hydrochloride injection was found to be physically compatible and chemically stable in the following parenteral solutions for at least 24 hours when stored in glass or polyvinylchloride (PVC) bags at controlled room temperature 15º-30°C (59°-86°F) or under refrigeration 2°-8°C (36°-46°F).

• dextrose (5%) injection
• sodium chloride (0.9%) injection
• dextrose (5%) and sodium chloride (0.45%) injection

Physical Incompatibilities

Because of potential physical incompatibilities, it is recommended that diltiazem hydrochloride not be mixed with any other drugs in the same container. If possible, it is recommended that diltiazem hydrochloride not be co-infused in the same intravenous line.

Physical incompatibilities (precipitate formation or cloudiness) were observed when diltiazem hydrochloride injection was infused in the same intravenous line with the following drugs: acetazolamide, acyclovir, aminophylline, ampicillin, ampicillin sodium/sulbactam sodium, cefamandole, cefoperazone, diazepam, furosemide, hydrocortisone sodium succinate, insulin (regular: 100 units/mL), methylprednisolone sodium succinate, mezlocillin, nafcillin, phenytoin, rifampin, and sodium bicarbonate.

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

Transition to Further Antiarrhythmic Therapy

Transition to other antiarrhythmic agents following administration of diltiazem hydrochloride injection is generally safe. However, reference should be made to the respective agent manufacturer’s package insert for information relative to dosage and administration.

In controlled clinical trials, therapy with antiarrhythmic agents to maintain reduced heart rate in atrial fibrillation or atrial flutter or for prophylaxis of PSVT was generally started within 3 hours after bolus administration of diltiazem hydrochloride. These antiarrhythmic agents were intravenous or oral digoxin, Class 1 antiarrthythmics (e.g., quinidine, procainamide), calcium channel blockers, and oral beta-blockers.

Experience in the use of antiarrhythmic agents following maintenance infusion of diltiazem hydrochloride injection is limited. Patients should be dosed on an individual basis and reference should be made to the respective manufacturer’s package insert for information relative to dosage and administration.