rease 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.

traindicated. 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.

njection 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. dilution to prepare diltiazem hydrochloride injection for continuous intravenous infusion, aseptically transfer the appropriate quantity (see chart) of diltiazem hydrochloride injection to the desired volume of either normal saline, d5w, or d5w/0.45% nacl. mix thoroughly. use within 24 hours. keep refrigerated until use. * 5 mg/h may be appropriate for some patients 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. dosage

llowing events were reported infrequently (less than 1%): 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. cardiovascular av block (third degree), bundle branch block, ecg abnormality, palpitations, syncope, tachycardia, ventricular extrasystoles. dermatologic alopecia, erythema multiforme (including stevens-johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, leukocytoclastic vasculitis, petechiae, photosensitivity, purpura, rash, urticaria. gastrointestinal anorexia, diarrhea, dysgeusia, dyspepsia, mild elevations of sgpt and ldh, thirst, weight increase. nervous system abnormal dreams, amnesia, depression, extrapyramidal symptoms, gait abnormality, hallucinations, insomnia, nervousness, personality change, somnolence, tremor. other allergic reactions, angioedema (including facial or periorbital edema), cpk elevation, epistaxis, eye irritation, gingival hyperplasia, hemolytic anemia, hyperglycemia, impotence, increased bleeding time, leukopenia, muscle cramps, myopathy, nasal congestion, nocturia, osteoarticular pain, polyuria, retinopathy, sexual difficulties, thrombocytopenia, tinnitus. events such as myocardial infarction have been observed which are not readily distinguishable from the natural history of the disease for the patient.

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.