DILTIAZEM HYDROCHLORIDE in SODIUM CHLORIDE

1 INDICATIONS AND USAGE Diltiazem Hydrochloride in Sodium Chloride Injection is a non-dihydropyridine calcium-channel blocker indicated for the following: • Temporary control of rapid ventricular rate in atrial fibrillation or atrial flutter. ( 1.1) • Rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm. ( 1.2 ) 1.1 Atrial Fibrillation or Atrial Flutter Diltiazem Hydrochloride in Sodium Chloride Injection is indicated in adults for the temporary control of rapid ventricular rate in atrial fibrillation or atrial flutter. 1.2 Paroxysmal Supraventricular Tachycardia Diltiazem Hydrochloride in Sodium Chloride Injection is indicated in adults for rapid conversion of paroxysmal supraventricular tachycardias (PSVT) to sinus rhythm.

2 DOSAGE AND ADMINISTRATION Monitor ECG and blood pressure. The initial dose is 0.25 mg/kg or 20 mg intravenously over 2 minutes. If response is inadequate at 15 minutes, give one or more doses of 0.35 mg/kg or 25 mg intravenously over 2 minutes. Immediately following first bolus administration, begin intravenous infusion at 5 mg/hour. Increase by 5 mg/hour up to 15 mg/hour as needed and tolerated. ( 2.1 , 2.2 , 2.3 ) Do not mix with other drugs. ( 2.4 ) 2.1 General Considerations Administer intravenous diltiazem in a setting with continuous monitoring of the ECG and frequent measurement of blood pressure. A defibrillator and emergency equipment should be readily available. Diltiazem Hydrochloride in Sodium Chloride Injection is a ready to administer product that requires no further dilution prior to infusion. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. 2.2 Intravenous Single Injection The initial dose of diltiazem hydrochloride should be 0.25 mg/kg actual body weight 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 dose of diltiazem hydrochloride 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. 2.3 Continuous Intravenous Infusion Immediately following bolus, the recommended initial infusion rate of diltiazem hydrochloride is 5 mg/hour. Adjust the infusion rate in 5 mg/hour increments up to a maximum of 15 mg/hour as needed to achieve satisfactory rate control. Infusions longer than 24 hours have not been studied. Patients should generally be transitioned to other antiarrhythmic agents within 24 hours [see Clinical Studies ( 14 )] . 2.4 Physical Incompatibilities Do not mix diltiazem hydrochloride with any other drugs in the same container. If possible, use a dedicated line for diltiazem hydrochloride. Diltiazem hydrochloride has demonstrated physical incompatibilities with 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.

4 CONTRAINDICATIONS Diltiazem Hydrochloride in Sodium Chloride Injection is contraindicated in the following situations: • Patients with sick sinus syndrome or second- or third-degree AV block except in the presence of a functioning ventricular pacemaker. • Patients with severe hypotension or cardiogenic shock. • Patients who have demonstrated hypersensitivity to the drug. • Concomitant administration with IV beta-blockers. • Patients with atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in WPW syndrome. • Patients with ventricular tachycardia. • Sick sinus syndrome or second- or third-degree AV block with no functioning ventricular pacemaker. ( 4 ) • Severe hypotension or cardiogenic shock. ( 4 ) • Demonstrated hypersensitivity to the drug. ( 4 ) • Atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in Wolff-Parkinson-White (WPW). ( 4 ) • Ventricular tachycardia. ( 4 )

5 WARNINGS AND PRECAUTIONS • Hemodynamic deterioration and ventricular fibrillation if administered to patients with wide complex tachycardia of ventricular origin. ( 5.2 ) • Second-or third-degree AV block. ( 5.3 ) • Heart failure. ( 5.4 ) • Hypotension. ( 5.5 ) 5.1 Tachycardia and Hypotension in patients with AF/AFL and accessory bypass tract Diltiazem may cause ventricular fibrillation if given to patients in atrial fibrillation or atrial flutter associated with an accessory bypass tract such as in WPW syndrome. Distinguish atrial fibrillation with aberrancy (bundle branch block) from pre-excited atrial fibrillation prior to diltiazem administration [see Contraindications (4)] . 5.2 Hemodynamic Deterioration in Patients with Wide Complex Tachycardia Diltiazem may cause hemodynamic deterioration and ventricular fibrillation if administered to patients with wide complex tachycardia of ventricular origin. Distinguish wide complex QRS tachycardia of supraventricular origin from that of ventricular origin prior to diltiazem administration [see Contraindications ( 4 )]. 5.3 AV Block Diltiazem prolongs AV nodal conduction and refractoriness that may cause 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 Drug Interactions ( 7 )] . If high-degree AV block occurs in sinus rhythm, discontinue diltiazem and institute appropriate supportive measures [see Overdosage ( 10 )]. 5.4 Heart Failure Diltiazem is a negative inotrope and can cause decreased systolic function and heart failure. Do not initiate in patients with acute decompensated heart failure or cardiogenic shock. If heart failure develops during diltiazem treatment, discontinue treatment and treat heart failure appropriately. 5.5 Hypotension Diltiazem can cause symptomatic hypotension. Patients with low blood pressure at baseline and those on concomitant medications that decrease blood pressure, intravascular volume, or myocardial contractility are at increased risk for hypotension.

7 DRUG INTERACTIONS Table 1. Clinically Relevant Interactions with Diltiazem Drug/Substance Class or Name Clinical implication Prevention/Management Agents Known to decrease peripheral resistance, cardiac contractility or conduction Increased risk of bradycardia, AV block, and heart failure. Monitor. Beta-blockers Increased risk of bradycardia, AV block, and depression of contractility. Beta-blocker may need to be decreased [see Warnings and Precautions (5.1, 5.2)]. Anesthetics Depressed cardiac contractility, conductivity, and automaticity as well as the vascular dilation. Monitor. Clonidine Increased risk of bradycardia. Monitor . Drugs metabolized by Cytochrome P450 3A4 Diltiazem is both a substrate and an inhibitor of the cytochrome P450 3A4 enzyme system. Concomitant use with diltiazem can increase exposure of drugs that are substrates of CYP450 3A4. Drugs that are substrates of CYP450 3A4 may require dose adjustment to maintain optimum therapeutic blood levels. Benzodiazepines Increased exposure likely. Monitor. Buspirone Carbamazepine Cyclosporine Quinidine Ranolazine Limit ranolazine to 500 mg twice daily. Statins Increased risk of myopathy and rhabdomyolysis with statins metabolized by CYP3A4. When possible, use a non-CYP3A4-metabolized statin with diltiazem. Limit daily dose of simvastatin to 10 mg and diltiazem to 240 mg [see Clinical Pharmacology (12.3)]. Ivabradine May exacerbate bradycardia and conduction disturbances. Avoid concomitant use [see Clinical Pharmacology (12.3)] . Effect of other drugs on Diltiazem Cytochrome P450 3A4 Inhibitors/ Inducers Diltiazem is a substrate of the cytochrome P450 3A4 enzyme and inhibitors/inducers may change the pharmacological effect of diltiazem Monitor. Strong or moderate CYP 3A inhibitors a Examples b : Ketoconazole, itraconazole, cimetidine Patients currently receiving diltiazem therapy should be carefully monitored for a change in pharmacological effect when initiating and discontinuing therapy with strong or moderate inhibitors of CYP3A4. An adjustment in the diltiazem dose may be warranted CYP inducers Examples b : Rifampin, carbamazepine CYP3A inducers can lower the plasma levels of diltiazem. Coadministration of diltiazem with rifampin or any known CYP3A4 inducer should be avoided when possible, and alternative therapy considered [see Clinical Pharmacology (12.3)]. a Strong and moderate inhibitors increase the AUC of sensitive substrates of CYP3A4 by ≥ 5 and ≥ 2-fold, respectively b These examples are a guide and not considered a comprehensive list of all possible drugs that may fit this category. The healthcare provider should consult appropriate references for comprehensive information. • Anesthetics: Further depression of cardiac contractility, conductivity, and automaticity as well as vascular dilation. ( 7 ) • Beta-Blockers: Monitor for bradycardia, AV block, and depression of contractility. ( 7 ) • Clonidine: Increased risk of bradycardia. ( 7 ) • CYP3A4 Inducers: Avoid concomitant use. ( 7 ) • CYP3A4 Inhibitors: Monitor diltiazem’s pharmacologic effect. ( 7 ) • CYP3A4: substrates: Increased exposure of substrates. ( 7 ) • Ivabradine: Avoid concomitant use. ( 7 ) • Ranolazine: Limit ranolazine to 500 mg twice daily. ( 7 ) • Statins: Avoid statins metabolized by CYP3A4. ( 7 )

6 ADVERSE REACTIONS 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. Hypotension was the most commonly reported adverse event during clinical trials, with symptomatic hypotension occurring in 3.2% of patients. Other events reported in a 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%): Gastrointestinal - Constipation, elevated SGOT or alkaline phosphatase, nausea, vomiting Nervous System - Dizziness Other - dyspnea, edema, headache, Although not observed in clinical trials with diltiazem hydrochloride injection, the following events associated with oral diltiazem may occur: Dermatologic - Erythema multiforme (including Stevens-Johnson syndrome, toxic epidermal necrolysis), exfoliative dermatitis, petechiae, photosensitivity, purpura, pruritus, rash, urticaria, acute generalized exanthematous pustulosis, Gastrointestinal - Anorexia, dysgeusia, dyspepsia Other - Allergic reactions, angioedema (including facial or periorbital edema), gingival hyperplasia, hyperglycemia, impotence. Most common adverse reactions are hypotension, itching and burning at injection site, vasodilation, and arrhythmia. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact WG Critical Care, LLC at 1-866-562-4708, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

8.1 Pregnancy Risk Summary The available data from the published literature over decades of use with diltiazem during pregnancy have not identified a drug associated risk of major birth defects, miscarriage, or adverse maternal or fetal outcomes. In animal reproduction studies, decreased embryo and fetal survival rates, and skeletal abnormalities have been observed at oral doses five to ten times the human oral antianginal therapeutic dose, and reduction in pup weights was also observed. At 20 times the human oral antianginal therapeutic dose, an increase in stillbirths was observed (see Data) . The estimated background risk for major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively. Data Animal Data Reproduction studies have been conducted in mice, rats, and rabbits. Administration of oral doses ranging from five to ten times greater (on a mg/kg basis) than the human oral antianginal therapeutic dose has resulted in embryo and fetal lethality. These doses, in some studies, have been reported to cause skeletal abnormalities. In the perinatal/postnatal studies there was some reduction in early individual pup weights and survival rates. There was an increased incidence of stillbirths at doses of 20 times the human oral antianginal therapeutic dose or greater.