DILTIAZEM HYDROCHLORIDE INJECTION
Action And Clinical Pharmacology: Diltiazem inhibits the influx of calcium 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 atrioventricular (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 (AF/FL). 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. lt has no effects on the sinus node recovery time or on the sinoatrial (SA) 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 administered i.v. 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. Following administration of 1 or 2 i.v. bolus doses of diltiazem, 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. 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 a limited number of studies of patients with compromised myocardiums (severe congestive heart failure, acute myocardial infarction, hypertrophic cardiomyopathy), administration of i.v. 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 pre-existing 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 and 300 ng/mL were determined to produce reductions in heart rate of 30 and 40%.
Pharmacokinetics: Following a single i.v. injection in healthy male volunteers, diltiazem appears to obey linear pharmacokinetics over a dose range of 10.5 to 21.0 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 i.v. 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 AF/FL, diltiazem systemic clearance has been found to be decreased compared to healthy volunteers. In patients administered bolus doses ranging from 2.5 to 38.5 mg, systemic clearance averaged 36 L/h. In patients administered continuous infusions at 10 or 15 mg/h for 24 hours, diltiazem systemic clearance averaged 42 L/h and 31 L/h, respectively.
The metabolic pathways of diltiazem metabolism include N-and O-demethylation (via cytochrome P450), deacetylation (via plasma and tissue esterases), in addition to conjugation (via sulfation and glucuronidation). In vitro studies have demonstrated that CYP 3A4 is the principal CYP isoenzyme involved in N-demethylation. Metabolites N-monodesmethyldiltiazem, and desacetyldiltiazem, desacetyl-N-monodesmethyldiltiazem, desacetyl-O-desmethyldiltiazem, and desacetyl-N, O-desmethyldiltiazem have been identified in human urine following oral administration. With 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 i.v. injection of diltiazem, however, plasma concentrations of N-monodesmethyldiltiazem and desacetyldiltiazem, 2 principal metabolites found in plasma after oral administration, are typically not detected. These metabolites are observed, however, following 24-hour constant rate i.v. infusion.
Total radioactivity measurement following short i.v. administration in healthy volunteers suggests the presence of other unidentified metabolites which attain higher concentrations than those of diltiazem and are more slowly eliminated. Plasma half-life of total radioactivity is about 20 hours compared to 2 to 5 hours for diltiazem.
Diltiazem is 70 to 80% bound to plasma proteins.
Indications And Clinical Uses: 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 AF/FL associated with an accessory bypass tract such as in Wolff-Parkinson-White (WPW) syndrome, or short PR syndrome, e.g., Lown-Ganong-Levine syndrome. Diltiazem injection rarely converts atrial fibrillation or atrial flutter to normal sinus rhythm.
Paroxysmal Supraventricular Tachycardia: Rapid conversion of paroxysmal supraventricular tachycardias 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, e.g., Lown-Ganong-Levine syndrome. Unless otherwise contraindicated, appropriate vagal manoeuvres should be attempted prior to administration of diltiazem injection.
The use of diltiazem injection for control of ventricular response in patients with atrial fibrillation or atrial flutter or conversion to sinus rhythm in patients with paroxysmal supraventricular tachycardia 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 the setting should include continuous monitoring of the ECG and frequent measurement of blood pressure. A defibrillator and emergency equipment should be readily available.
Contra-Indications: Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker. Patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker. Patients with known hypersensitivity to diltiazem. Patients with severe hypotension or cardiogenic shock.
In patients with AF/FL associated with an accessory bypass tract such as in WPW syndrome, or short PR syndrome, e.g., Lown-Ganong-Levine syndrome. As with other agents which slow AV nodal conduction and do not prolong the refractoriness of the accessory pathway (e.g., verapamil, digoxin), in rare instances patients with AF/FL associated with an accessory bypass tract may experience a potentially life-threatening increase in heart rate accompanied by hypotension when treated with diltiazem injection.
In patients with ventricular tachycardia. Administration of other calcium channel blockers to patients with wide complex tachycardia (QRS Â³0.12 seconds) has resulted in hemodynamic deterioration and ventricular fibrillation. It is important that an accurate pretreatment diagnosis distinguish wide complex QRS tachycardia of supraventricular origin from that of ventricular origin prior to administration of diltiazem injection.
Pregnancy: In pregnancy and in women of childbearing potential. Fetal malformations and adverse effects on pregnancy have been reported in animals. In repeated dose studies, a high incidence of vertebral column malformations was present in the offspring of mice receiving more than 50 mg/kg of diltiazem orally.
I.V. diltiazem and i.v. beta-blockers should not be administered together or in close proximity (within a few hours).
Manufacturers’ Warnings In Clinical States: Cardiac Conduction: Diltiazem injection 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, i.v. diltiazem should be discontinued and appropriate supportive measures instituted (see Overdose: Symptoms and Treatment).
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 is contraindicated in myocardial infarction patients who have left ventricular failure manifested by pulmonary congestion. Experience with the use of diltiazem 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 injection therapy may occasionally result in symptomatic hypotension (see Adverse Effects). In controlled clinical trials, 3.2% of patients required some form of intervention (use of i.v. fluids, or the Trendelenburg position) for blood pressure support following diltiazem injection.
The use of i.v. 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 of enzymes such as alkaline phosphatase, LDH, AST, ALT, and symptoms consistent with acute hepatic injury have been noted following oral diltiazem. Although a causal relationship to diltiazem has not been established in all cases, a drug induced hypersensitivity reaction is suspected (see Adverse Effects). Therefore, the potential for acute hepatic injury exists following administration of i.v. diltiazem.
Ventricular Premature Beats (VPBs): VPBs may be present on conversion of PSVT to sinus rhythm with i.v. diltiazem. 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.
Precautions: Impaired Hepatic or Renal Function: Diltiazem 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. Liver cirrhosis was shown to reduce apparent oral diltiazem clearance, prolong the half-life of orally administered diltiazem and increase its bioavailability by 69%.
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 Disorders: Dermatologic events progressing to erythema multiforme and/or exfoliative dermatitis have been infrequently reported following oral diltiazem (see Adverse Effects). Therefore, the potential for these dermatologic reactions exists following exposure to i.v. diltiazem. Should a dermatologic reaction persist, the drug should be discontinued.
Drug Interactions: Due to potential for additive effects, caution is warranted in patients receiving diltiazem concomitantly with any agent(s) known to affect cardiac contractility and/or SA or AV node conduction (see Warnings).
As with all drugs, care should be exercised when treating patients with multiple medications. Calcium channel blockers undergo biotransformation by the cytochrome P450 system. Coadministration of diltiazem with other drugs which follow the same route of biotransformation may result in altered bioavailability. Dosages of similarly metabolized drugs, particularly those of low therapeutic ratio, and especially in patients with renal and/or hepatic impairment, may require adjustment when starting or stopping concomitantly administered diltiazem to maintain optimum therapeutic blood levels.
Drugs known to be inhibitors of the cytochrome P450 system include: azole antifungals, cimetidine, cyclosporine, erythromycin, quinidine, warfarin.
Drugs known to be inducers of the cytochrome P450 system include: phenobarbital, phenytoin, rifampin.
Drugs known to be biotransformed via P450 include: benzodiazepines, flecainide, imipramine, propafenone, terfenadine, theophylline.
Anesthetics: The depression of cardiac contractility, conductivity, and automaticity as well as the vascular dilation associated with anesthetics may be potentiated by calcium channel blockers. When used concomitantly, anesthetics and calcium blockers should be titrated carefully.
Benzodiazepines: Diltiazem significantly increases peak plasma levels and the elimination half-life of triazolam and midazolam.
Beta-Blockers: I.V. diltiazem has been administered to patients on chronic oral beta-blocker therapy. The combination of the 2 drugs was generally well tolerated without serious adverse effects.
If i.v. diltiazem is administered to patients receiving chronic oral beta-blocker therapy, the possibility for bradycardia, AV block, and/or depression of contractility should be considered (see Contraindications). Oral administration of diltiazem with propranolol in 5 normal volunteers resulted in increased propranolol levels in all subjects and bioavailability of propranolol was increased approximately 50%. In vitro, propranolol appears to be displaced from its binding sites by diltiazem.
Carbamazepine: Concomitant administration of diltiazem with carbamazepine has been reported to result in elevated serum levels of carbamazepine (40 to 72% increase) resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction.
Cimetidine: A study in 6 healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and AUC (53%) after a 1-week course of cimetidine at 1 200 mg/day and a single dose of oral diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with cimetidine. An adjustment in the diltiazem dose may be warranted.
Cyclosporine: A pharmacokinetic interaction between diltiazem and cyclosporine has been observed during studies involving renal and cardiac transplant patients. In renal and cardiac transplant recipients, a reduction of cyclosporine dose ranging from 15 to 48% was necessary to maintain cyclosporine trough concentrations similar to those seen prior to the addition of diltiazem. If these agents are to be administered concurrently, cyclosporine concentrations should be monitored, especially when diltiazem therapy is initiated, adjusted or discontinued. The effect of cyclosporine on diltiazem plasma concentrations has not been evaluated.
Digitalis: I.V. diltiazem has been administered to patients receiving either i.v. or oral digitalis therapy. The combination of the 2 drugs was well tolerated without serious adverse effects. However, since both drugs affect AV nodal conduction, patients should be monitored for excessive slowing of the heart rate and/or AV block.
Rifampin: Administration of diltiazem with rifampin markedly reduced plasma diltiazem concentrations and the therapeutic effect of diltiazem.
Short and Long-acting Nitrates: Diltiazem may be safely coadministered with nitrates, but there have been few controlled studies to evaluate the antianginal effectiveness of this combination.
Other Calcium Antagonists: Limited clinical experience suggests that in certain severe conditions not responding adequately to verapamil or to nifedipine, using diltiazem in conjunction with either of these drugs may be beneficial.
Lactation: 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.
Children: Safety and effectiveness in children have not been established.
Adverse Reactions: Adverse reactions were derived from controlled clinical trials in 411 patients with paroxysmal supraventricular tachycardia, atrial fibrillation, or atrial flutter. Adverse reactions were reported in 17.3% of patients with injectable diltiazem, and required discontinuation of treatment in 1.5% of patients.
Worldwide experience in over 1 300 patients was similar. The most common adverse reactions (incidence of at least 1%) were: hypotension 7.5%, symptomatic hypotension 3.2%, injection site reaction (e.g., itching, burning) 3.9%, vasodilation (flushing) 1.7%, and arrhythmia (junctional rhythm or isorhythmic dissociation) 1.0%.
In addition, the following events were reported in less than 1% of cases:
Cardiovascular: atrial flutter, first-degree AV block, second-degree AV block, bradycardia, chest pain, congestive heart failure, sinus pause, sinus node dysfunction, syncope, ventricular arrhythmia, ventricular fibrillation, ventricular tachycardia.
Dermatologic: pruritus, sweating.
Gastrointestinal: constipation, elevated AST or alkaline phosphatase, nausea, vomiting.
Nervous system: dizziness, paresthesia.
Other: amblyopia, asthenia, dry mouth, dyspnea, general edema, headache, hyperuricemia.
Although not observed in clinical trials with injectable diltiazem, other reactions associated with oral diltiazem have been reported:
Cardiovascular: third-degree AV block, bundle branch block, ECG abnormality, palpitations, syncope, tachycardia, ventricular extrasystoles.
Dermatologic: alopecia, erythema multiforme, exfoliative dermatitis, leukocytoclastic vasculitis, petechiae, photosensitivity, purpura, rash, urticaria.
Gastrointestinal: anorexia, diarrhea, dysgeusia, dyspepsia, mild elevations of ALT and LDH, thirst, weight increase.
Nervous system: abnormal dreams, amnesia, depression, extrapyramidal symptoms, gait abnormality, hallucinations, insomnia, nervousness, personality change, somnolence, tremor.
Other: CPK elevation, detached retina, epistaxis, eye irritation, gingival hyperplasia, hemolytic anemia, hyperglycemia, impotence, increased bleeding time, leukopenia, muscle cramps, 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.
Symptoms And Treatment Of Overdose: Symptoms and Treatment: Overdosage experience is limited. ln the event of overdosage or an exaggerated response, appropriate supportive measures should be employed. The following measures may be considered:
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 norepinephrine).
The effectiveness of i.v. 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 i.v. calcium. In some cases i.v. 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/h 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.
The i.v. LD50’s in mice and rats were 58 to 61 and 38 to 39 mg/kg, respectively. The toxic dose in man is not known.
Dosage And Administration: Direct I.V. Single Injection (Bolus): The initial dose of diltiazem injection should be 0.25 mg/kg as a bolus administered over 2 minutes. If response is inadequate, a second dose may be administered after 15 minutes. The second bolus dose should be 0.35 mg/kg administered over 2 minutes. Subsequent i.v. bolus doses should be individualized for each patient. Some patients may respond to an initial dose of 0.15 mg/kg, although duration of action may be shorter.
Continuous I.V. Infusion: For continued reduction of the heart rate (up to 24 hours) in patients with AF/FL, an i.v. infusion of diltiazem may be administered. Immediately following bolus administration of 0.25 or 0.35 mg/kg, and reduction in heart rate, begin an i.v. infusion of diltiazem. The recommended initial infusion rate is 10 mg/h. The infusion rate may be increased 5 to 15 mg/h as needed, if further reduction in heart rate is required. Some patients may maintain response to an initial rate of 5 mg/h. The infusion may be maintained for up to 24 hours.
Diltiazem shows dose-dependent, nonlinear pharmacokinetics during continuous i.v. infusion. 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 for continuous i.v. infusion, aseptically transfer the appropriate quantity of diltiazem i.v. injection to the desired volume of either Normal Saline, D5W, or D5W/0.45% NaCl. Mix thoroughly. Use within 24 hours. Keep refrigerated (2 to 8°C) until use.
Diltiazem injection was tested for compatibility with 3 commonly used i.v. fluids at a maximal concentration of 1 mg diltiazem/mL. Diltiazem 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 in polyvinylchloride (PVC) bags at a controlled room temperature of 15 to 30Â°C or under refrigeration at 2 to 8Â°C: Dextrose (5%) Injection, USP; Sodium Chloride (0.9%) Injection, USP; Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP.
Because of potential physical incompatibilities, diltiazem injection should not be mixed with any other drugs in the same container.
Therefore, it is recommended that diltiazem injection not be coinfused in the same i.v. line.
Physical incompatibilities (precipitate formation or cloudiness) were observed when diltiazem injection was infused in the same i.v. 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: Experience in the use of antiarrhythmic agents following diltiazem injection is limited. In controlled clinical trials, therapy with antiarrhythmic agents to maintain reduced heart rate in atrial fibrillation or atrial flutter, or for prophylaxis of paroxysmal supraventricular tachycardia was generally started within 3 hours after bolus administration. Patients should be dosed on an individual basis and reference should be made to the respective manufacturer’s product monograph for information relative to dosage and administration of antiarrhythmic agents.
Availability And Storage: Each mL contains: diltiazem HCl 5 mg. Nonmedicinal ingredients: citric acid monohydrate, sodium citrate dihydrate, sorbitol solution and water for injection up to 1 mL. Sodium hydroxide and/or hydrochloric acid may be used for pH adjustment. Preservative-free. Vials of 5 mL, cartons of 10. Vials of 10 mL, cartons of 10.
Store under refrigeration, at 2 to 8°C. Do not freeze. It may be stored at room temperature for up to 1 month. Destroy after 1 month at room temperature.
Dilution for Continuous I.V. Infusion: To prepare diltiazem for continuous i.v. infusion, refer to Dosage section for diluent volumes, compatibility with i.v. fluids and stability of dilutions.
I.V. admixtures should be inspected visually for clarity, particulate matter, precipitate, discoloration and leakage prior to administration whenever solution and container permit.
DILTIAZEM HYDROCHLORIDE INJECTION Novopharm Antiarrhythmic
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