ADVERSE REACTIONS SECTION.

6 ADVERSE REACTIONS. Most common adverse reactions (incidence> 10%) are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension (6)To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.. 6.1 Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.The following adverse reaction rates are based on use of esmolol hydrochloride injection in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important and common adverse effect has been hypotension [see Warnings and Precautions (5.1)]. Deaths have been reported in post-marketing experience occurring during complex clinical states where esmolol hydrochloride injection was presumably being used simply to control ventricular rate [see Warnings and Precautions (5.5)].Table Clinical Trial Adverse Reactions (Frequency >=3%) System Organ Class (SOC)Preferred MedDRA TermFrequencyVASCULAR DISORDERSHypotensionAsymptomatic hypotension25%Symptomatic hypotension(hyperhidrosis, dizziness)12%GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONSInfusion site reactions(inflammation and induration)8%GASTROINTESTINAL DISORDERSNausea7%NERVOUS SYSTEM DISORDERSDizziness3%Somnolence3% Hypotension resolved during esmolol hydrochloride infusion in 63% of patients. In 80% of the remaining patients, hypotension resolved within 30 minutes following discontinuation of infusion. Clinical Trial Adverse Reactions (Frequency <3%). Psychiatric DisordersConfusional state and agitation (~2%)Anxiety, depression and abnormal thinking (<1%)Nervous System DisordersHeadache (~ 2%)Paresthesia, syncope, speech disorder, and lightheadedness (<1%)Convulsions (<1%), with one deathVascular DisordersPeripheral ischemia (~1%)Pallor and flushing (<1%)Gastrointestinal DisordersVomiting (~1%)Dyspepsia, constipation, dry mouth, and abdominal discomfort (<1%)Renal and Urinary DisordersUrinary retention (<1%). 6.2 Post-Marketing Experience. In addition to the adverse reactions reported in clinical trials, the following adverse reactions have been reported in the post-marketing experience. Because these reactions are reported voluntarily from population of uncertain size, it is not always possible to estimate reliably their frequency or to establish causal relationship to drug exposure.Cardiac DisordersCardiac arrest, Coronary arteriospasmSkin and Subcutaneous Tissue DisordersAngioedema, Urticaria, Psoriasis.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1 Mechanism of Action. Esmolol hydrochloride injection is beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, very short duration of action, and no significant intrinsic sympathomimetic or membrane stabilizing activity at therapeutic dosages. Its elimination half-life after intravenous infusion is approximately minutes. Esmolol hydrochloride injection inhibits the beta1 receptors located chiefly in cardiac muscle, but this preferential effect is not absolute and at higher doses it begins to inhibit beta2 receptors located chiefly in the bronchial and vascular musculature.. 12.2 Pharmacodynamics. Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of esmolol hydrochloride injection, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of esmolol hydrochloride injection have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes. The acid metabolite of esmolol exhibits negligible pharmacological activity.In human electrophysiology studies, esmolol hydrochloride injection produced effects typical of beta blocker: decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length.In patients undergoing radionuclide angiography, esmolol hydrochloride injection, at dosages of 200 mcg/kg/min, produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During exercise, esmolol hydrochloride injection produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but esmolol hydrochloride injection produced significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min of esmolol hydrochloride injection produced similar effects and, in addition, there were small, clinically insignificant increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure. At 30 minutes after the discontinuation of esmolol hydrochloride infusion, all of the hemodynamic parameters had returned to pretreatment levels.The relative cardioselectivity of esmolol hydrochloride injection was demonstrated in 10 mildly asthmatic patients. Infusions of esmolol hydrochloride injection 100, 200 and 300 mcg/kg/min produced no significant increases in specific airway resistance compared to placebo. At 300 mcg/kg/min, esmolol hydrochloride injection produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and esmolol hydrochloride injection was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at dosage of mg, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of esmolol hydrochloride injection for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients).. 12.3 Pharmacokinetics. Esmolol is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of esmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolol has rapid distribution half-life of about minutes and an elimination half-life of about minutes.Using an appropriate loading dose, steady-state blood levels of esmolol hydrochloride injection for dosages from 50-300 mcg/kg/min are obtained within five minutes. Steady-state is reached in about 30 minutes without the loading dose. Steady-state blood levels of esmolol increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of esmolol can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion.Consistent with the high rate of blood-based metabolism of esmolol, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, the acid metabolite of esmolol in urine accounts for approximately 73-88% of the dosage.Metabolism of esmolol results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have negligible activity and in normal volunteers its blood levels do not correspond to the level of beta blockade. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with clearance approximately equivalent to the glomerular filtration rate. After 4 hour maintenance infusion of 150 mcg/kg, the plasma concentrations of esmolol are similar in subjects with normal renal function and in patients with ESRD on dialysis. The half-life of the acid metabolite of esmolol hydrochloride injection, which is primarily excreted unchanged by the kidney, is increased about 12-fold to 48 hours in patients with ESRD. The peak concentrations of the acid metabolite are doubled in ESRD.Methanol blood levels, monitored in subjects receiving esmolol hydrochloride injection for up to hours at 300 mcg/kg/min and 24 hours at 150 mcg/kg/min, approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity.Esmolol hydrochloride has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. Supraventricular TachycardiaIn two multicenter, randomized, double-blind, controlled comparisons of esmolol hydrochloride injection with placebo and propranolol, maintenance doses of 50 to 300 mcg/kg/min of esmolol hydrochloride injection were found to be more effective than placebo and about as effective as propranolol, 3-6 mg given by bolus injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation and atrial flutter. The majority of these patients developed their arrhythmias postoperatively. About 60-70% of the patients treated with esmolol hydrochloride injection developed either 20% reduction in heart rate, decrease in heart rate to less than 100 bpm, or, rarely, conversion to normal sinus rhythm and about 95% of these patients did so at dosage of 200 mcg/kg/min or less. The average effective dosage of esmolol hydrochloride injection was approximately 100 mcg/kg/min in the two studies. Other multicenter baseline-controlled studies gave similar results. In the comparison with propranolol, about 50% of patients in both the esmolol hydrochloride injection and propranolol groups were on concomitant digoxin. Response rates were slightly higher with both beta blockers in the digoxin-treated patients.In all studies significant decreases of blood pressure occurred in 20-50% of patients, identified either as adverse reaction reports by investigators, or by observation of systolic pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension was symptomatic (mainly hyperhidrosis or dizziness) in about 12% of patients, and therapy was discontinued in about 11% of patients, about half of whom were symptomatic. Hypotension was more common with esmolol hydrochloride injection (53%) than with propranolol (17%). The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with esmolol hydrochloride injection. For both esmolol hydrochloride injection and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin.

CONTRAINDICATIONS SECTION.

4 CONTRAINDICATIONS. Esmolol hydrochloride injection is contraindicated in patients with:oSevere sinus bradycardia: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].oHeart block greater than first degree: Second- or third-degree atrioventricular block may precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].oSick sinus syndrome: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].oDecompensated heart failure: May worsen heart failure.oCardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest.oIV administration of cardiodepressant calcium-channel antagonists (e.g., verapamil) and esmolol hydrochloride injection in close proximity (i.e., while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving esmolol hydrochloride injection and intravenous verapamil.oPulmonary hypertension: May precipitate cardiorespiratory compromise.oHypersensitivity reactions, including anaphylaxis, to esmolol or any of the inactive ingredients of the product (cross-sensitivity between beta blockers is possible).. oSevere sinus bradycardia: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].. oHeart block greater than first degree: Second- or third-degree atrioventricular block may precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].. oSick sinus syndrome: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)].. oDecompensated heart failure: May worsen heart failure.. oCardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest.. oIV administration of cardiodepressant calcium-channel antagonists (e.g., verapamil) and esmolol hydrochloride injection in close proximity (i.e., while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving esmolol hydrochloride injection and intravenous verapamil.. oPulmonary hypertension: May precipitate cardiorespiratory compromise.. oHypersensitivity reactions, including anaphylaxis, to esmolol or any of the inactive ingredients of the product (cross-sensitivity between beta blockers is possible).. oSevere sinus bradycardia (4)oHeart block greater than first degree (4)oSick sinus syndrome (4)oDecompensated heart failure (4)oCardiogenic shock (4)oCoadministration of IV cardiodepressant calcium-channel antagonists (e.g. verapamil) in close proximity to esmolol hydrochloride injection (4, 7)oPulmonary hypertension (4) oKnown hypersensitivity to esmolol (4). oSevere sinus bradycardia (4). oHeart block greater than first degree (4). oSick sinus syndrome (4). oDecompensated heart failure (4). oCardiogenic shock (4). oCoadministration of IV cardiodepressant calcium-channel antagonists (e.g. verapamil) in close proximity to esmolol hydrochloride injection (4, 7). oPulmonary hypertension (4) oKnown hypersensitivity to esmolol (4).

DESCRIPTION SECTION.

11 DESCRIPTION. Esmolol hydrochloride injection is beta adrenergic receptor blocker with very short duration of action (elimination half-life is approximately minutes). Esmolol hydrochloride injection is:o(+-)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure:oEsmolol hydrochloride injection has the empirical formula C16H26NO4Cl and molecular weight of 331.8. It has one asymmetric center and exists as an enantiomeric pair.oEsmolol hydrochloride is white to off-white crystalline powder. It is relatively hydrophilic compound which is very soluble in water and freely soluble in alcohol. Its partition coefficient (octanol/water) at pH 7.0 is 0.42 compared to 17.0 for propranolol.. o(+-)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure:. oEsmolol hydrochloride injection has the empirical formula C16H26NO4Cl and molecular weight of 331.8. It has one asymmetric center and exists as an enantiomeric pair.. oEsmolol hydrochloride is white to off-white crystalline powder. It is relatively hydrophilic compound which is very soluble in water and freely soluble in alcohol. Its partition coefficient (octanol/water) at pH 7.0 is 0.42 compared to 17.0 for propranolol.. 11.1 Esmolol Hydrochloride Injection Dosage Forms. Esmolol Hydrochloride Injection is clear, colorless to light yellow, sterile, nonpyrogenic, iso-osmotic solution of esmolol hydrochloride injection in sodium chloride. The formulation is described in the table below:Table Formulation for Esmolol Hydrochloride Injection Esmolol Hydrochloride. USP10 mg/mLSodium Chloride, USP5.9 mg/mLWater for Injection, USPQ.S. to volume of 10 mLSodium Acetate Trihydrate, USP2.8 mg/mLGlacial Acetic Acid, USP0.546 mg/mLSodium HydroxideQ.S. to adjust pH to 4.5-5.5Hydrochloric AcidQ.S. to adjust pH to 4.5-5.5Q.S. Quantity sufficient. Esmolol Hydrochloride Structural Formula.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. oAdminister intravenously (2.1, 2.2)oTitrate using ventricular rate or blood pressure at >=4-minute intervals. (2.1, 2.2)oSupraventricular tachycardia (SVT) or noncompensatory sinus tachycardia (2.1)oOptional loading dose: 500 mcg per kg infused over one minuteoThen 50 mcg per kg per minute for the next minutesoAdjust dose as needed to maximum of 200 mcg per kg per minute. oAdditional loading doses may be administered oPerioperative tachycardia and hypertension (2.2)o Loading dose: 500 mcg per kg over minute for gradual control (1 mg per kg over 30 seconds for immediate control)o Then 50 mcg per kg per min for gradual control (150 mcg per kg per minute for immediate control) adjusted to maximum of 200 (tachycardia) or 300 (hypertension) mcg per kg per min (2.2). oAdminister intravenously (2.1, 2.2). oTitrate using ventricular rate or blood pressure at >=4-minute intervals. (2.1, 2.2). oSupraventricular tachycardia (SVT) or noncompensatory sinus tachycardia (2.1)oOptional loading dose: 500 mcg per kg infused over one minuteoThen 50 mcg per kg per minute for the next minutesoAdjust dose as needed to maximum of 200 mcg per kg per minute. oAdditional loading doses may be administered oOptional loading dose: 500 mcg per kg infused over one minute. oThen 50 mcg per kg per minute for the next minutes. oAdjust dose as needed to maximum of 200 mcg per kg per minute. oAdditional loading doses may be administered oPerioperative tachycardia and hypertension (2.2)o Loading dose: 500 mcg per kg over minute for gradual control (1 mg per kg over 30 seconds for immediate control)o Then 50 mcg per kg per min for gradual control (150 mcg per kg per minute for immediate control) adjusted to maximum of 200 (tachycardia) or 300 (hypertension) mcg per kg per min (2.2). Loading dose: 500 mcg per kg over minute for gradual control (1 mg per kg over 30 seconds for immediate control). Then 50 mcg per kg per min for gradual control (150 mcg per kg per minute for immediate control) adjusted to maximum of 200 (tachycardia) or 300 (hypertension) mcg per kg per min (2.2). 2.1 Dosing for the Treatment of Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia. Esmolol hydrochloride injection is administered by continuous intravenous infusion with or without loading dose. Additional loading doses and/or titration of the maintenance infusion (step-wise dosing) may be necessary based on desired ventricular response.Table Step-Wise Dosing StepAction1Optional loading dose (500 mcg per kg over minute), then 50 mcg per kg per min for min2Optional loading dose if necessary, then 100 mcg per kg per min for min3Optional loading dose if necessary, then 150 mcg per kg per min for min4If necessary, increase dose to 200 mcg per kg per minIn the absence of loading doses, continuous infusion of single concentration of esmolol reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes. The effective maintenance dose for continuous and step-wise dosing is 50 to 200 mcg per kg per minute, although doses as low as 25 mcg per kg per minute have been adequate. Dosages greater than 200 mcg per kg per minute provide little added heart rate lowering effect, and the rate of adverse reactions increases.Maintenance infusions may be continued for up to 48 hours.. 2.2 Intraoperative and Postoperative Tachycardia and Hypertension. In this setting it is not always advisable to slowly titrate to therapeutic effect. Therefore two dosing options are presented: immediate control and gradual control.. Immediate Control. oAdminister mg per kg as bolus dose over 30 seconds followed by an infusion of 150 mcg per kg per min if necessary.oAdjust the infusion rate as required to maintain desired heart rate and blood pressure. Refer to Maximum Recommended Doses below.. oAdminister mg per kg as bolus dose over 30 seconds followed by an infusion of 150 mcg per kg per min if necessary.. oAdjust the infusion rate as required to maintain desired heart rate and blood pressure. Refer to Maximum Recommended Doses below.. Gradual Control oAdminister 500 mcg per kg as bolus dose over minute followed by maintenance infusion of 50 mcg per kg per min for minutes.oDepending on the response obtained, continue dosing as outlined for supraventricular tachycardia. Refer to Maximum Recommended Doses below.. oAdminister 500 mcg per kg as bolus dose over minute followed by maintenance infusion of 50 mcg per kg per min for minutes.. oDepending on the response obtained, continue dosing as outlined for supraventricular tachycardia. Refer to Maximum Recommended Doses below.. Maximum Recommended Doses. oFor the treatment of tachycardia, maintenance infusion dosages greater than 200 mcg per kg per min are not recommended; dosages greater than 200 mcg per kg per min provide little additional heart rate-lowering effect, and the rate of adverse reactions increases.oFor the treatment of hypertension, higher maintenance infusion dosages (250-300 mcg per kg per min) may be required. The safety of doses above 300 mcg per kg per minute has not been studied.. oFor the treatment of tachycardia, maintenance infusion dosages greater than 200 mcg per kg per min are not recommended; dosages greater than 200 mcg per kg per min provide little additional heart rate-lowering effect, and the rate of adverse reactions increases.. oFor the treatment of hypertension, higher maintenance infusion dosages (250-300 mcg per kg per min) may be required. The safety of doses above 300 mcg per kg per minute has not been studied.. 2.3 Transition from Esmolol Hydrochloride Injection Therapy to Alternative Drugs. After patients achieve adequate control of the heart rate and stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished.When transitioning from esmolol hydrochloride injection to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of esmolol hydrochloride injection as follows:1.Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride infusion rate by one-half (50%).2.After administration of the second dose of the alternative drug, monitor the patients response and if satisfactory control is maintained for the first hour, discontinue the esmolol hydrochloride infusion.. 1.Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride infusion rate by one-half (50%).. 2.After administration of the second dose of the alternative drug, monitor the patients response and if satisfactory control is maintained for the first hour, discontinue the esmolol hydrochloride infusion.. 2.4 Directions for Use. This dosage form is prediluted to provide ready-to-use, iso-osmotic solution of 10 mg/mL esmolol hydrochloride in sodium chloride recommended for esmolol hydrochloride intravenous administration. The ready-to-use vial may be used to administer loading dosage by hand-held syringe while the maintenance infusion is being prepared.When using 10 mg/mL concentration, loading dose of 0.5 mg/kg infused over minute, for 70 kg patient is 3.5 mL.Esmolol hydrochloride injection is not compatible with Sodium Bicarbonate (5%) solution (limited stability) or furosemide (precipitation).Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.. Compatibility with Commonly Used Intravenous Fluids. Esmolol hydrochloride injection was tested for compatibility with ten commonly used intravenous fluids at final concentration of 10 mg esmolol hydrochloride per mL. Esmolol hydrochloride injection was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature or under refrigeration:oDextrose (5%) Injection, USPoDextrose (5%) in Lactated Ringers InjectionoDextrose (5%) in Ringers InjectionoDextrose (5%) and Sodium Chloride (0.45%) Injection, USPoDextrose (5%) and Sodium Chloride (0.9%) Injection, USPoLactated Ringers Injection, USPoPotassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USPoSodium Chloride (0.45%) Injection, USPoSodium Chloride (0.9%) Injection, USP. oDextrose (5%) Injection, USP. oDextrose (5%) in Lactated Ringers Injection. oDextrose (5%) in Ringers Injection. oDextrose (5%) and Sodium Chloride (0.45%) Injection, USP. oDextrose (5%) and Sodium Chloride (0.9%) Injection, USP. oLactated Ringers Injection, USP. oPotassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USP. oSodium Chloride (0.45%) Injection, USP. oSodium Chloride (0.9%) Injection, USP.

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. Concomitant use of esmolol hydrochloride injection with other drugs that can lower blood pressure, reduce myocardial contractility, or interfere with sinus node function or electrical impulse propagation in the myocardium can exaggerate esmolol hydrochloride injections effects on blood pressure, contractility, and impulse propagation. Severe interactions with such drugs can result in, for example, severe hypotension, cardiac failure, severe bradycardia, sinus pause, sinoatrial block, atrioventricular block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate increased withdrawal effects. (See clonidine, guanfacine, and moxonidine below.) Esmolol hydrochloride injection should therefore be used only after careful individual assessment of the risks and expected benefits in patients receiving drugs that can cause these types of pharmacodynamic interactions, including but not limited to:oDigitalis glycosides: Concomitant administration of digoxin and esmolol hydrochloride injection leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect esmolol hydrochloride injection pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia.oAnticholinesterases: Esmolol hydrochloride injection prolonged the duration of succinylcholine-induced neuromuscular blockade and moderately prolonged clinical duration and recovery index of mivacurium. oAntihypertensive agents clonidine, guanfacine, or moxonidine: Beta blockers also increase the risk of clonidine-, guanfacine-, or moxonidine-withdrawal rebound hypertension. If, during concomitant use of beta blocker, antihypertensive therapy needs to be interrupted or discontinued, discontinue the beta blocker first, and the discontinuation should be gradual.oCalcium channel antagonists: In patients with depressed myocardial function, use of esmolol hydrochloride injection with cardiodepressant calcium channel antagonists (e.g., verapamil) can lead to fatal cardiac arrests.oSympathomimetic drugs: Sympathomimetic drugs having beta-adrenergic agonist activity will counteract effects of esmolol hydrochloride injection. oVasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular resistance, do not use esmolol hydrochloride injection to control tachycardia in patients receiving drugs that are vasoconstrictive and have positive inotropic effects, such as epinephrine, norepinephrine, and dopamine.. oDigitalis glycosides: Concomitant administration of digoxin and esmolol hydrochloride injection leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect esmolol hydrochloride injection pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia.. oAnticholinesterases: Esmolol hydrochloride injection prolonged the duration of succinylcholine-induced neuromuscular blockade and moderately prolonged clinical duration and recovery index of mivacurium. oAntihypertensive agents clonidine, guanfacine, or moxonidine: Beta blockers also increase the risk of clonidine-, guanfacine-, or moxonidine-withdrawal rebound hypertension. If, during concomitant use of beta blocker, antihypertensive therapy needs to be interrupted or discontinued, discontinue the beta blocker first, and the discontinuation should be gradual.. oCalcium channel antagonists: In patients with depressed myocardial function, use of esmolol hydrochloride injection with cardiodepressant calcium channel antagonists (e.g., verapamil) can lead to fatal cardiac arrests.. oSympathomimetic drugs: Sympathomimetic drugs having beta-adrenergic agonist activity will counteract effects of esmolol hydrochloride injection. oVasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular resistance, do not use esmolol hydrochloride injection to control tachycardia in patients receiving drugs that are vasoconstrictive and have positive inotropic effects, such as epinephrine, norepinephrine, and dopamine.. oDigitalis glycosides: Risk of bradycardia (7)oAnticholinesterases: Prolongs neuromuscular blockade (7)oAntihypertensive agents: Risk of rebound hypertension (7)oSympathomimetic drugs: Dose adjustment needed (7)oVasoconstrictive and positive inotropic effect substances: Avoid concomitant use (7) oDigitalis glycosides: Risk of bradycardia (7). oAnticholinesterases: Prolongs neuromuscular blockade (7). oAntihypertensive agents: Risk of rebound hypertension (7). oSympathomimetic drugs: Dose adjustment needed (7). oVasoconstrictive and positive inotropic effect substances: Avoid concomitant use (7).

INDICATIONS & USAGE SECTION.

1 INDICATIONS AND USAGE. Esmolol hydrochloride injection is beta adrenergic blocker indicated for the short-term treatment of: oControl of ventricular rate in supraventricular tachycardia including atrial fibrillation and atrial flutter and control of heart rate in noncompensatory sinus tachycardia (1.1)oControl of perioperative tachycardia and hypertension (1.2). oControl of ventricular rate in supraventricular tachycardia including atrial fibrillation and atrial flutter and control of heart rate in noncompensatory sinus tachycardia (1.1). oControl of perioperative tachycardia and hypertension (1.2). 1.1 Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia. Esmolol hydrochloride injection is indicated for the rapid control of ventricular rate in patients with atrial fibrillation or atrial flutter in perioperative, postoperative, or other emergent circumstances where short term control of ventricular rate with short-acting agent is desirable. Esmolol hydrochloride injection is also indicated in noncompensatory sinus tachycardia where, in the physicians judgment, the rapid heart rate requires specific intervention. Esmolol hydrochloride injection is intended for short-term use.. 1.2 Intraoperative and Postoperative Tachycardia and/or Hypertension. Esmolol hydrochloride injection is indicated for the short-term treatment of tachycardia and/or hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia and in the postoperative period, when in the physicians judgment such specific intervention is considered indicated.Use of esmolol hydrochloride injection to prevent such events is not recommended.

OVERDOSAGE SECTION.

10 OVERDOSAGE. 10.1 Signs and Symptoms of Overdose. Overdoses of esmolol hydrochloride injection can cause cardiac and central nervous system effects. These effects may precipitate severe signs, symptoms, sequelae, and complications (for example, severe cardiac and respiratory failure, including shock and coma), and may be fatal. Continuous monitoring of the patient is required.oCardiac effects include bradycardia, atrioventricular block (1st -, 2nd -, 3rd degree), junctional rhythms, intraventricular conduction delays, decreased cardiac contractility, hypotension, cardiac failure (including cardiogenic shock), cardiac arrest/asystole, and pulseless electrical activity.oCentral nervous system effects include respiratory depression, seizures, sleep and mood disturbances, fatigue, lethargy, and coma.oIn addition, bronchospasm, mesenteric ischemia, peripheral cyanosis, hyperkalemia, and hypoglycemia (especially in children) may occur.. oCardiac effects include bradycardia, atrioventricular block (1st -, 2nd -, 3rd degree), junctional rhythms, intraventricular conduction delays, decreased cardiac contractility, hypotension, cardiac failure (including cardiogenic shock), cardiac arrest/asystole, and pulseless electrical activity.. oCentral nervous system effects include respiratory depression, seizures, sleep and mood disturbances, fatigue, lethargy, and coma.. oIn addition, bronchospasm, mesenteric ischemia, peripheral cyanosis, hyperkalemia, and hypoglycemia (especially in children) may occur.. 10.2 Treatment Recommendations. Because of its approximately 9-minute elimination half-life, the first step in the management of toxicity should be to discontinue the esmolol hydrochloride infusion. Then, based on the observed clinical effects, consider the following general measures.BradycardiaConsider intravenous administration of atropine or another anticholinergic drug or cardiac pacing.Cardiac FailureConsider intravenous administration of diuretic or digitalis glycoside. In shock resulting from inadequate cardiac contractility, consider intravenous administration of dopamine, dobutamine, isoproterenol, or inamrinone. Glucagon has been reported to be useful.Symptomatic hypotensionConsider intravenous administration of fluids or vasopressor agents such as dopamine or norepinephrine.BronchospasmConsider intravenous administration of beta2 stimulating agent or theophylline derivative.. 10.3 Dilution Errors. Massive accidental overdoses of esmolol hydrochloride injection have resulted from dilution errors. Use of BREVIBLOC PREMIXED Injection and BREVIBLOC PREMIXED Double Strength Injection may reduce the potential for dilution errors. Some of these overdoses have been fatal while others resulted in permanent disability. Bolus doses in the range of 625 mg to 2.5 (12.5-50 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1.75 given over one minute or doses of 7.5 given over one hour for cardiovascular surgery. The patients who survived appear to be those whose circulation could be supported until the effects of esmolol hydrochloride injection resolved.

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

PRINCIPAL DISPLAY PANEL PACKAGING LABELING. Container Label NDC 10019-120-39EsmololHydrochlorideInjection100 mg/10 mL(10 mg/mL)Rx only10 mLReady-to-use VialFOR INTRAVENOUS USEIso-OsmoticContains no preservatives discardunused portion.For Product Inquiry1 800 ANA DRUG (1-800-262-3784)Manufactured forBaxter Healthcare CorporationDeerfield, IL 60015 USACarton LabelLOT: EXP:NDC 10019-120-01EsmololHydrochloride Injection 100 mg/10 mL (10 mg/mL) Rx only 25 10 mL Ready-to-use VialsFOR INTRAVENOUS USESingle Dose Vials. Iso-OsmoticContains no preservatives discard unused portion.BaxterManufactured for Baxter Healthcare CorporationDeerfield, IL 60015 USA 460-812-01Each mL contains: 10 mg Esmolol Hydrochloride, USP and 5.9 mg Sodium Chloride, USP in Water for Injection, USP. Buffered with Sodium Acetate Trihydrate, USP and Glacial Acetic Acid, USP. Sodium Hydroxide and/or Hydrochloric Acid added to adjust pH to 5.0 (range 4.5-5.5).Store at 25C (77F). Excursions permitted to 15-30C(59-86F). [See USP Controlled Room Temperature.]Avoid contact with alkalies. Do not use if discolored or if aprecipitate is present.See package insert for complete information on dosage and administration.For Product Inquiry 800 ANA DRUG (1-800-262-3784)07-04-73-1093 10019 12001 0NDC 10019-120-01EsmololHydrochloride Injection100 mg/10 mL (10 mg/mL) Store at 25C (77F)4 packs each containing25 10 mL Ready-to-use Vials475-775-01Bar CodeEXP DEC2099 LOT ABCDE12345 QTY 4Bar Code(17)991231(10)ABCDE12345(30)4Bar Code(01)50310019120015(21)00000000000001Manufactured forBaxter Healthcare CorporationDeerfield, IL 60015 USA. Esmolol Container Label. Esmolol Representative Carton Label NDC 10019-120-01. Representative Shipper Label 10019-120-01.

PHARMACODYNAMICS SECTION.

12.2 Pharmacodynamics. Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of esmolol hydrochloride injection, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of esmolol hydrochloride injection have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes. The acid metabolite of esmolol exhibits negligible pharmacological activity.In human electrophysiology studies, esmolol hydrochloride injection produced effects typical of beta blocker: decrease in the heart rate, increase in sinus cycle length, prolongation of the sinus node recovery time, prolongation of the AH interval during normal sinus rhythm and during atrial pacing, and an increase in antegrade Wenckebach cycle length.In patients undergoing radionuclide angiography, esmolol hydrochloride injection, at dosages of 200 mcg/kg/min, produced reductions in heart rate, systolic blood pressure, rate pressure product, left and right ventricular ejection fraction and cardiac index at rest, which were similar in magnitude to those produced by intravenous propranolol (4 mg). During exercise, esmolol hydrochloride injection produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but esmolol hydrochloride injection produced significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min of esmolol hydrochloride injection produced similar effects and, in addition, there were small, clinically insignificant increases in the left ventricular end diastolic pressure and pulmonary capillary wedge pressure. At 30 minutes after the discontinuation of esmolol hydrochloride infusion, all of the hemodynamic parameters had returned to pretreatment levels.The relative cardioselectivity of esmolol hydrochloride injection was demonstrated in 10 mildly asthmatic patients. Infusions of esmolol hydrochloride injection 100, 200 and 300 mcg/kg/min produced no significant increases in specific airway resistance compared to placebo. At 300 mcg/kg/min, esmolol hydrochloride injection produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and esmolol hydrochloride injection was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at dosage of mg, two experienced significant, symptomatic bronchospasm requiring bronchodilator treatment. One other propranolol-treated patient also experienced dry air-induced bronchospasm. No adverse pulmonary effects were observed in patients with COPD who received therapeutic dosages of esmolol hydrochloride injection for treatment of supraventricular tachycardia (51 patients) or in perioperative settings (32 patients).

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. Esmolol is rapidly metabolized by hydrolysis of the ester linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma cholinesterases or red cell membrane acetylcholinesterase. Total body clearance in man was found to be about 20 L/kg/hr, which is greater than cardiac output; thus the metabolism of esmolol is not limited by the rate of blood flow to metabolizing tissues such as the liver or affected by hepatic or renal blood flow. Esmolol has rapid distribution half-life of about minutes and an elimination half-life of about minutes.Using an appropriate loading dose, steady-state blood levels of esmolol hydrochloride injection for dosages from 50-300 mcg/kg/min are obtained within five minutes. Steady-state is reached in about 30 minutes without the loading dose. Steady-state blood levels of esmolol increase linearly over this dosage range and elimination kinetics are dose-independent over this range. Steady-state blood levels are maintained during infusion but decrease rapidly after termination of the infusion. Because of its short half-life, blood levels of esmolol can be rapidly altered by increasing or decreasing the infusion rate and rapidly eliminated by discontinuing the infusion.Consistent with the high rate of blood-based metabolism of esmolol, less than 2% of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion, the acid metabolite of esmolol in urine accounts for approximately 73-88% of the dosage.Metabolism of esmolol results in the formation of the corresponding free acid and methanol. The acid metabolite has been shown in animals to have negligible activity and in normal volunteers its blood levels do not correspond to the level of beta blockade. The acid metabolite has an elimination half-life of about 3.7 hours and is excreted in the urine with clearance approximately equivalent to the glomerular filtration rate. After 4 hour maintenance infusion of 150 mcg/kg, the plasma concentrations of esmolol are similar in subjects with normal renal function and in patients with ESRD on dialysis. The half-life of the acid metabolite of esmolol hydrochloride injection, which is primarily excreted unchanged by the kidney, is increased about 12-fold to 48 hours in patients with ESRD. The peak concentrations of the acid metabolite are doubled in ESRD.Methanol blood levels, monitored in subjects receiving esmolol hydrochloride injection for up to hours at 300 mcg/kg/min and 24 hours at 150 mcg/kg/min, approximated endogenous levels and were less than 2% of levels usually associated with methanol toxicity.Esmolol hydrochloride has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. 8.1 Pregnancy. Esmolol hydrochloride injection has been shown to produce increased fetal resorptions with minimal maternal toxicity in rabbits when given in doses approximately times the maximum human maintenance dose (300 mcg/kg/min). There are no adequate and well-controlled studies in pregnant women. Esmolol hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Teratogenicity studies in rats at intravenous dosages of esmolol hydrochloride injection up to 3000 mcg/kg/min (10 times the maximum human maintenance dosage) for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while dosage of 10,000 mcg/kg/min produced maternal toxicity and lethality. In rabbits, intravenous dosages up to 1000 mcg/kg/min for 30 minutes daily produced no evidence of maternal toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min produced minimal maternal toxicity and increased fetal resorptions.. 8.2 Labor and Delivery. Although there are no adequate and well-controlled studies in pregnant women, use of Esmolol hydrochloride injection in the last trimester of pregnancy or during labor or delivery has been reported to cause fetal bradycardia, which continued after termination of drug infusion. Esmolol hydrochloride injection should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.. 8.3 Nursing Mothers. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from esmolol hydrochloride injection, decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.. 8.4 Pediatric Use. The safety and effectiveness of esmolol hydrochloride injection in pediatric patients have not been established.. 8.5 Geriatric Use. Clinical studies of esmolol hydrochloride injection did not include sufficient numbers of subjects aged 65 and over to determine whether they responded 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 usually start at the low end of the dosing range, reflecting greater frequency of decreased renal or cardiac function and of concomitant disease or other drug therapy.. 8.6 Hepatic Impairment. No special precautions are necessary in patients with hepatic impairment because esmolol hydrochloride injection is metabolized by red-blood cell esterases [see Clinical Pharmacology (12)]. 8.7 Renal Impairment. No dosage adjustment is required for Esmolol hydrochloride injection in patients with renal impairment receiving maintenance infusion of esmolol hydrochloride injection 150 mcg/kg for hours. There is no information on the tolerability of maintenance infusions of esmolol hydrochloride injection using rates in excess of 150 mcg/kg or maintained longer than hours [see Clinical Pharmacology (12)].

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. oRisk of hypotension, bradycardia, and cardiac failure: Reduce or discontinue use (5.1, 5.2, 5.3, 5.10)oRisk of exacerbating reactive airway disease (5.5)oDiabetes mellitus: Increases the effect of hypoglycemic agents and masks hypoglycemic tachycardia (5.6)oRisk of unopposed alpha-agonism and severe hypertension in untreated pheochromocytoma (5.9)oRisk of myocardial ischemia when abruptly discontinued in patients with coronary artery disease (5.12, 5.15). oRisk of hypotension, bradycardia, and cardiac failure: Reduce or discontinue use (5.1, 5.2, 5.3, 5.10). oRisk of exacerbating reactive airway disease (5.5). oDiabetes mellitus: Increases the effect of hypoglycemic agents and masks hypoglycemic tachycardia (5.6). oRisk of unopposed alpha-agonism and severe hypertension in untreated pheochromocytoma (5.9). oRisk of myocardial ischemia when abruptly discontinued in patients with coronary artery disease (5.12, 5.15). 5.1 Hypotension. Hypotension can occur at any dose but is dose-related. Patients with hemodynamic compromise or on interacting medications are at particular risk. Severe reactions may include loss of consciousness, cardiac arrest, and death. For control of ventricular heart rate, maintenance doses greater than 200 mcg per kg per min are not recommended. Monitor patients closely, especially if pretreatment blood pressure is low. In case of an unacceptable drop in blood pressure, reduce or stop esmolol hydrochloride injection. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes.. 5.2 Bradycardia. Bradycardia, including sinus pause, heart block, severe bradycardia, and cardiac arrest have occurred with the use of esmolol hydrochloride injection. Patients with first-degree atrioventricular block, sinus node dysfunction, or conduction disorders may be at increased risk. Monitor heart rate and rhythm in patients receiving esmolol hydrochloride injection [see Contraindications (4)].If severe bradycardia develops, reduce or stop esmolol hydrochloride injection.. 5.3 Cardiac Failure. Beta blockers, like esmolol hydrochloride injection, can cause depression of myocardial contractility and may precipitate heart failure and cardiogenic shock. At the first sign or symptom of impending cardiac failure, stop esmolol hydrochloride and start supportive therapy [see Overdosage (10)].. 5.4 Intraoperative and Postoperative Tachycardia and/or Hypertension. Monitor vital signs closely and titrate esmolol hydrochloride injection slowly in the treatment of patients whose blood pressure is primarily driven by vasoconstriction associated with hypothermia.. 5.5 Reactive Airways Disease. Patients with reactive airways disease should, in general, not receive beta blockers. Because of its relative beta1 selectivity and titratability, titrate esmolol hydrochloride injection to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; beta2 stimulating agent may be administered with appropriate monitoring of ventricular rates.. 5.6 Use in Patients with Diabetes Mellitus and Hypoglycemia. In patients with hypoglycemia, or diabetic patients (especially those with labile diabetes) who are receiving insulin or other hypoglycemic agents, beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be masked.Concomitant use of beta blockers and antidiabetic agents can enhance the effect of antidiabetic agents (blood glucose-lowering).. 5.7 Infusion Site Reactions. Infusion site reactions have occurred with the use of esmolol hydrochloride injection. They include irritation, inflammation, and severe reactions (thrombophlebitis, necrosis, and blistering), in particular when associated with extravasation [see Adverse Reactions (6)]. Avoid infusions into small veins or through butterfly catheter.If local infusion site reaction develops, use an alternative infusion site and avoid extravasation.. 5.8 Use in Patients with Prinzmetals Angina. Beta blockers may exacerbate anginal attacks in patients with Prinzmetals angina because of unopposed alpha receptor-mediated coronary artery vasoconstriction. Do not use nonselective beta blockers.. 5.9 Use in Patients with Pheochromocytoma. If esmolol hydrochloride injection is used in the setting of pheochromocytoma, give it in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with paradoxical increase in blood pressure from the attenuation of beta-mediated vasodilation in skeletal muscle.. 5.10 Use in Hypovolemic Patients. In hypovolemic patients, esmolol hydrochloride injection can attenuate reflex tachycardia and increase the risk of hypotension.. 5.11 Use in Patients with Peripheral Circulatory Disorders. In patients with peripheral circulatory disorders (including Raynauds disease or syndrome, and peripheral occlusive vascular disease), esmolol hydrochloride injection may aggravate peripheral circulatory disorders.. 5.12 Abrupt Discontinuation of Esmolol Hydrochloride Injection. Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing esmolol hydrochloride injection.Heart rate increases moderately above pretreatment levels 30 minutes after esmolol hydrochloride injection discontinuation.. 5.13 Hyperkalemia. Beta blockers, including esmolol hydrochloride injection, have been associated with increases in serum potassium levels and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment. Intravenous administration of beta blockers has been reported to cause potentially life-threatening hyperkalemia in hemodialysis patients. Monitor serum electrolytes during therapy with esmolol hydrochloride injection.. 5.14 Use in Patients with Metabolic Acidosis. Beta blockers, including esmolol hydrochloride injection, have been reported to cause hyperkalemic renal tubular acidosis. Acidosis in general may be associated with reduced cardiac contractility.. 5.15 Use in Patients with Hyperthyroidism. Beta-adrenergic blockade may mask certain clinical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta blocking therapy.. 5.16 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions. When using beta blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic).Patients using beta blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions [see Drug Interactions (7)].