DILTIAZEM HYDROCHLORIDE

Diltiazem hydrochloride is a calcium ion cellular influx inhibitor (slow channel blocker or calcium channel antagonist). Chemically, diltiazem hydrochloride is 1,5-benzothiazepin-4(5 H )-one, 3-(acetyloxy)-5-[2-(dimethylamino)ethyl]-2, 3-dihydro-2-(4-methoxyphenyl)-, monohydrochloride,(+)-cis-. The chemical structure is: Diltiazem hydrochloride is a white to off-white crystalline powder with a bitter taste. It is soluble in water, methanol, and chloroform. It has a molecular weight of 450.98. Diltiazem hydrochloride injection is a clear, colorless, sterile, nonpyrogenic solution. It has a pH range of 3.7 to 4.1. Diltiazem hydrochloride injection is for direct intravenous bolus injection and continuous intravenous infusion. 25-mg, 5-mL vial-each sterile vial contains 25 mg diltiazem hydrochloride, 3.75 mg citric acid USP, 3.25 mg sodium citrate dihydrate USP, 250 mg sorbitol NF and water for injection USP up to 5 mL. Sodium hydroxide or hydrochloric acid is used for pH adjustment. 50-mg, 10-mL vial-each sterile vial contains 50 mg diltiazem hydrochloride, 7.5 mg citric acid USP, 6.5 mg sodium citrate dihydrate USP, 500 mg sorbitol NF and water for injection USP up to 10 mL. Sodium hydroxide or hydrochloric acid is used for pH adjustment. Diltiazem hydrochloride for injection is an off-white lyophilized powder and, after reconstitution in an infusion bag, produces a clear, colorless, sterile, nonpyrogenic solution. Diltiazem hydrochloride for injection for continuous intravenous infusion is available in ADD-Vantage Vials. The vial contains lyophilized powder comprised of diltiazem hydrochloride 100 mg and mannitol USP 75 mg for reconstitution in the ADD-Vantage Flexible Diluent Container containing 5% dextrose injection or 0.9% sodium chloride injection. Chemical Structure

Diltiazem Hydrochloride Injection or Diltiazem Hydrochloride for Injection are indicated for the following: 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. In addition, Diltiazem Hydrochloride Injection is indicated for: 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 or diltiazem hydrochloride for 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 hydrochloride 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 hydrochloride 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.

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 or diltiazem hydrochloride for injection may be administered. (For reconstitution of diltiazem hydrochloride for injection, see instructions contained within packaging.) 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 injection or diltiazem hydrochloride for injection. The recommended initial infusion rate of diltiazem hydrochloride injection or diltiazem hydrochloride for injection 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 to the desired volume of either Normal Saline, D5W, or D5W/0.45% NaCl. Mix thoroughly. Keep diluted diltiazem hydrochloride injection refrigerated until use. Use within 24 hours. To prepare diltiazem hydrochloride for injection for continuous intravenous infusion, assemble the ADD-Vantage vial as directed for use with either 0.9% Sodium Chloride or Dextrose (5%) injection. Mix thoroughly. Keep diluted diltiazem hydrochloride for injection at controlled room temperature 15° to 30°C (59° to 86°F) [See USP] or refrigerated 2° to 8°C (36° to 46°F) until use. Use within 24 hours. Diltiazem Hydrochloride Injection Diluent Volume Quantity of Diltiazem hydrochloride injection Final Concentration Administration Dose 5 mg/h may be appropriate for some patients Infusion Rate 100 mL 125 mg (25 mL) Final Volume 125 mL 1 mg/mL 10 mg/h 15 mg/h 10 mL/h 15 mL/h 250 mL 250 mg (50 mL) Final Volume 300 mL 0.83 mg/mL 10 mg/h 15 mg/h 12 mL/h 18 mL/h 500 mL 250 mg (50 mL) Final Volume 550 mL 0.45 mg/mL 10 mg/h 15 mg/h 22 mL/h 33 mL/h Diltiazem Hydrochloride for Injection Diluent Volume Quantity of Diltiazem hydrochloride injection Final Concentration Administration Dose 5 mg/h may be appropriate for some patients Infusion Rate 100 mL 100 mg (1 ADD-Vantage vial) 1 mg/mL 10 mg/h 15 mg/h 10 mL/h 15 mL/h

Injectable forms of diltiazem are contraindicated in: 1. Patients with sick sinus syndrome except in the presence of a functioning ventricular pacemaker. 2. Patients with second- or third-degree AV block except in the presence of a functioning ventricular pacemaker. 3. Patients with severe hypotension or cardiogenic shock. 4. Patients who have demonstrated hypersensitivity to the drug. 5. Intravenous diltiazem and intravenous beta-blockers should not be administered together or in close proximity (within a few hours). 6. Patients with atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in WPW syndrome or short PR 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 in atrial fibrillation or atrial flutter associated with an accessory bypass tract may experience a potentially life-threatening increase in heart rate accompanied by hypotension when treated with injectable forms of diltiazem. As such, the initial use of injectable forms of diltiazem should be, if possible, in a setting where monitoring and resuscitation capabilities, including DC cardioversion/defibrillation, are present (see OVERDOSAGE ). Once familiarity of the patient's response is established, use in an office setting may be acceptable. 7. Patients with ventricular tachycardia. Administration of other calcium channel blockers to patients with wide complex tachycardia (QRS ≥ 0.12 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 injectable forms of diltiazem.

The following adverse reaction rates are based on the use of diltiazem hydrochloride injection in over 400 domestic clinical trial patients with atrial fibrillation/flutter or PSVT under double-blind or open-label conditions. Worldwide experience in over 1,300 patients was similar. Adverse events reported in controlled and uncontrolled clinical trials were generally mild and transient. Hypotension was the most commonly reported adverse event during clinical trials. Asymptomatic hypotension occurred in 4.3% of patients. Symptomatic hypotension occurred in 3.2% of patients. When treatment for hypotension was required, it generally consisted of administration of saline or placing the patient in the Trendelenburg position. Other events reported in at least 1% of the diltiazem-treated patients were injection site reactions (e.g., itching, burning) - 3.9%, vasodilation (flushing) - 1.7%, and arrhythmia (junctional rhythm or isorhythmic dissociation) - 1%. In addition, the following 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: A cute generalized exanthematous pustulosis, 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, photosensitivity (including lichenoid keratosis and hyperpigmentation at sun-exposed skin areas), 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.

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. 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 Studies showed that diltiazem increased the AUC of midazolam and triazolam by 3- to 4-fold and C max by 2-fold, compared to placebo. The elimination half-life of midazolam and triazolam also increased (1.5- to 2.5-fold) during coadministration with diltiazem. These pharmacokinetic effects seen during diltiazem coadministration can result in increased clinical effects (e.g., prolonged sedation) of both midazolam and triazolam. Beta-blockers Intravenous diltiazem has been administered to patients on chronic oral beta-blocker therapy. The combination of the two drugs was generally well tolerated without serious adverse effects. If intravenous 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 five 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. Buspirone In nine healthy subjects, diltiazem significantly increased the mean buspirone AUC 5.5-fold and C max 4.1-fold compared to placebo. The T 1/2 and T max of buspirone were not significantly affected by diltiazem. Enhanced effects and increased toxicity of buspirone may be possible during concomitant administration with diltiazem. Subsequent dose adjustments may be necessary during coadministration, and should be based on clinical assessment. Carbamazepine Concomitant administration of oral diltiazem with carbamazepine has been reported to result in elevated plasma levels of carbamazepine (by 40 to 72%), resulting in toxicity in some cases. Patients receiving these drugs concurrently should be monitored for a potential drug interaction. Cimetidine A study in six healthy volunteers has shown a significant increase in peak diltiazem plasma levels (58%) and area-under-the-curve (53%) after a 1-week course of cimetidine at 1200 mg per day and a single dose of diltiazem 60 mg. Ranitidine produced smaller, nonsignificant increases. The effect may be mediated by cimetidine's known inhibition of hepatic cytochrome P-450, the enzyme system responsible for the first-pass metabolism of diltiazem. 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. Clonidine Sinus bradycardia resulting in hospitalization and pacemaker insertion has been reported in association with the use of clonidine concurrently with diltiazem. Monitor heart rate in patients receiving concomitant diltiazem and clonidine. 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 Intravenous diltiazem has been administered to patients receiving either intravenous or oral digitalis therapy. The combination of the two 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. Ivabradine Concurrent use of diltiazem increases exposure to ivabradine and may exacerbate bradycardia and conduction disturbances. Avoid concomitant use of ivabradine and diltiazem. Quinidine Diltiazem significantly increases the AUC (0→∞) of quinidine by 51%, T 1/2 by 36% and decreases its CL oral by 33%. Monitoring for quinidine adverse effects may be warranted and the dose adjusted accordingly. Rifampin Coadministration of rifampin with diltiazem lowered the diltiazem plasma concentrations to undetectable levels. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered. Statins Diltiazem is an inhibitor of CYP3A4 and has been shown to increase significantly the AUC of some statins. The risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4 may be increased with concomitant use of diltiazem. When possible, use a non-CYP3A4-metabolized statin together with diltiazem; otherwise, dose adjustments for both diltiazem and the statin should be considered along with close monitoring for signs and symptoms of any statin related adverse events. In a healthy volunteer cross-over study (N = 10), coadministration of a single 20 mg dose of simvastatin at the end of a 14-day regimen with 120 mg BID diltiazem SR resulted in a 5-fold increase in mean simvastatin AUC versus simvastatin alone. Subjects with increased average steady-state exposures of diltiazem showed a greater-fold increase in simvastatin exposure. Computer-based simulations showed that at a daily dose of 480 mg of diltiazem, an 8- to 9-fold mean increase in simvastatin AUC can be expected. If coadministration of simvastatin with diltiazem is required, limit the daily doses of simvastatin to 10 mg and diltiazem to 240 mg. In a ten-subject randomized, open label, 4-way cross-over study, coadministration of diltiazem (120 mg bid, diltiazem SR for 2 weeks) with a single 20 mg dose of lovastatin resulted in a 3- to 4-fold increase in mean lovastatin AUC and C max versus lovastatin alone. In the same study, there was no significant change in 20 mg single-dose pravastatin AUC and C max during diltiazem coadministration. Diltiazem plasma levels were not significantly affected by lovastatin or pravastatin.

DILTIAZEM HYDROCHLORIDE INJECTION IS TO BE STORED UNDER REFRIGERATION 2 TO 8°C (36 TO 46°F). DO NOT FREEZE. MAY BE STORED AT ROOM TEMPERATURE FOR UP TO 1 MONTH. DESTROY AFTER 1 MONTH AT ROOM TEMPERATURE. SINGLE-DOSE VIALS. DISCARD UNUSED PORTION. DILTIAZEM HYDROCHLORIDE FOR INJECTION IS TO BE STORED AT 20° TO 25°C (68° TO 77°F). [SEE USP CONTROLLED ROOM TEMPERATURE.] DO NOT FREEZE. RECONSTITUTED MATERIAL IS STABLE FOR 24 HOURS AT CONTROLLED ROOM TEMPERATURE OR REFRIGERATED 2° to 8°C (36° to 46°F). SINGLE-DOSE VIAL.