ESMOLOL HYDROCHLORIDE

Esmolol hydrochloride injection is a beta adrenergic receptor blocker with a very short duration of action (elimination half-life is approximately 9 minutes). Esmolol Hydrochloride is: (±)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure: Esmolol Hydrochloride has the molecular formula C16H26NO4Cl and a molecular weight of 331.8. It has one asymmetric center and exists as an enantiomeric pair. Esmolol Hydrochloride USP is a white to off-white crystalline powder. It is a 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 for propranolol. 11.1 Esmolol Hydrochloride Injection Dosage Form Esmolol hydrochloride injection is a clear, colorless to light yellow, sterile, nonpyrogenic solution of esmolol hydrochloride. The formulation for esmolol hydrochloride injection is described in the table below: Table 4 Esmolol Hydrochloride Injection Formulation Q.S. = Quantity sufficient STRUCTURE DESCRIPTION

INDICATIONS & USAGE 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 a short-acting agent is desirable. Esmolol hydrochloride injection is also indicated in noncompensatory sinus tachycardia where, in the physician’s judgment, the rapid heart rate requires specific intervention. Esmolol hydrochloride injection is intended for short-term use. 1.2 Intraoperative and Postoperative Tachycardia and Hypertension Esmolol hydrochloride injection is indicated for the short-term treatment of tachycardia and hypertension that occur during induction and tracheal intubation, during surgery, on emergence from anesthesia and in the postoperative period, when in the physician’s judgment such specific intervention is considered indicated. Use of esmolol hydrochloride injection to prevent such events is not recommended.

DOSAGE & ADMINISTRATION 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 a loading dose. Additional loading doses and/or titration of the maintenance infusion (step-wise dosing) may be necessary based on desired ventricular response. Table 1 Step-Wise Dosing In the absence of loading doses, continuous infusion of a 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 a therapeutic effect. Therefore two dosing options are presented: immediate control and gradual control. Immediate Control Administer 1 mg per kg as a bolus dose over 30 seconds followed by an infusion of 150 mcg per kg per min if necessary. Adjust the infusion rate as required to maintain desired heart rate and blood pressure. Refer to Maximum Recommended Doses below. Gradual Control Administer 500 mcg per kg as a bolus dose over 1 minute followed by a maintenance infusion of 50 mcg per kg per min for 4 minutes. Depending on the response obtained, continue dosing as outlined for supraventricular tachycardia (refer to Table 1). Refer to Maximum Recommended Doses below. Maximum Recommended Doses For 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. For the treatment of hypertension, higher maintenance infusion dosages (250 to 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 a 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 patient's response, and, if satisfactory control is maintained for the first hour, discontinue the esmolol hydrochloride infusion. 2.4 Directions for Use Esmolol hydrochloride injection is available in a single dose vial. 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. Single Dose Vial The Single Dose Vial may be used to administer a loading dosage by hand-held syringe while the maintenance infusion is being prepared. Compatibility with Commonly Used Intravenous Fluids Esmolol hydrochloride injection was tested for compatibility with ten commonly used intravenous fluids at a 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: Dextrose (5%) Injection, USP Dextrose (5%) in Lactated Ringer’s Injection Dextrose (5%) in Ringer’s Injection Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP Lactated Ringer’s Injection, USP Potassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USP Sodium Chloride (0.45%) Injection, USP Sodium Chloride (0.9%) Injection, USP DOSAGE

Esmolol hydrochloride injection is contraindicated in patients with: Severe sinus bradycardia: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)]. Heart 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)]. Sick sinus syndrome: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2)]. Decompensated heart failure: May worsen heart failure. Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest. IV administration of cardiodepressant calcium-channel antagonists (e.g., verapamil) and esmolol hydrochloride in close proximity (i.e., while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving esmolol hydrochloride and intravenous verapamil. Pulmonary hypertension: May precipitate cardiorespiratory compromise. Hypersensitivity reactions, including anaphylaxis, to esmolol or any of the inactive ingredients of the product (cross-sensitivity between beta blockers is possible).

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a 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 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 (5.3)]. Deaths have been reported in post-marketing experience occurring during complex clinical states where esmolol hydrochloride was presumably being used simply to control ventricular rate [see Warnings and Precautions (5.5)]. Table 3 Clinical Trial Adverse Reactions (Frequency ≥3%) * 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 Disorders Confusional state and agitation (~2%) Anxiety, depression and abnormal thinking (<1%) Nervous System Disorders Headache (~ 2%) Paresthesia, syncope, speech disorder, and lightheadedness (<1%) Convulsions (<1%), with one death Vascular Disorders Peripheral ischemia (~1%) Pallor and flushing (<1%) Gastrointestinal Disorders Vomiting (~1%) Dyspepsia, constipation, dry mouth, and abdominal discomfort have (<1%) Renal and Urinary Disorders Urinary 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 a population of uncertain size, it is not always possible to estimate reliably their frequency or to establish a causal relationship to drug exposure. Cardiac Disorders Cardiac arrest, Coronary arteriospasm Skin and Subcutaneous Tissue Disorders Angioedema, Urticaria, Psoriasis ADVERSE

Concomitant use of esmolol hydrochloride 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’s 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 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: Digitalis glycosides: Concomitant administration of digoxin and esmolol hydrochloride leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect esmolol hydrochloride pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia. Anticholinesterases: Esmolol hydrochloride prolonged the duration of succinylcholine-induced neuromuscular blockade and moderately prolonged clinical duration and recovery index of mivacurium. Antihypertensive agents clonidine, guanfacine, or moxonidine: Beta blockers also increase the risk of clonidine-, guanfacine-, or moxonidine-withdrawal rebound hypertension. If, during concomitant use of a beta blocker, antihypertensive therapy needs to be interrupted or discontinued, discontinue the beta blocker first, and the discontinuation should be gradual. Calcium channel antagonists: In patients with depressed myocardial infarction, use of esmolol hydrochloride with cardiodepressant calcium channel antagonists (e.g., verapamil) can lead to fatal cardiac arrests. Sympathomimetic drugs: Sympathomimetic drugs having beta-adrenergic agonist activity will counteract effects of esmolol hydrochloride. Vasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular resistance, do not use esmolol hydrochloride to control tachycardia in patients receiving drugs that are vasoconstrictive and have positive inotropic effects, such as epinephrine, norepinephrine, and dopamine.