ESMOLOL HYDROCHLORIDE

Esmolol hydrochloride 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 empirical formula C 16 H 26 NO 4 Cl and a molecular weight of 331.8. It has one asymmetric center and exists as an enantiomeric pair. Esmolol hydrochloride 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 17.0 for propranolol. Structural Formula 11.1 Esmolol Hydrochloride in Sodium Chloride Injection Dosage Forms All Esmolol Hydrochloride in Sodium Chloride Injection presentations are clear, colorless to light yellow, sterile, nonpyrogenic, iso-osmotic solutions of esmolol hydrochloride in sodium chloride. The formulations for Esmolol Hydrochloride in Sodium Chloride Injection and Esmolol Hydrochloride in Sodium Chloride Injection, Double Strength, are described in the table below: Table 4 Esmolol Hydrochloride in Sodium Chloride Injection Formulations Q.S. = Quantity Sufficient Esmolol Hydrochloride in Sodium Chloride Injection Esmolol Hydrochloride in Sodium Chloride Injection - Double Strength Esmolol Hydrochloride, USP 10 mg per mL 20 mg per mL Sodium Chloride, USP 5.9 mg per mL 4.1 mg per mL Water for Injection, USP Q.S. to volume of 250 mL Q.S. to volume of 100 mL Sodium Acetate Trihydrate, USP 2.8 mg per mL 2.8 mg per mL Glacial Acetic Acid, USP 0.546 mg per mL 0.546 mg per mL Sodium Hydroxide Q.S. to adjust pH to 4.5 to 5.5 Hydrochloric Acid Q.S. to adjust pH to 4.5 to 5.5 The calculated osmolarity of Esmolol Hydrochloride in Sodium Chloride Injection and Esmolol Hydrochloride in Sodium Chloride Injection, Double Strength, is 312 mOsmol/L. The 250 mL and 100 mL flexible container bags are not made with natural rubber latex and are PVC-free and DEHP-free with dual ports. Solutions in contact with the plastic container leach out certain chemical compounds from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials.

Esmolol Hydrochloride in Sodium Chloride Injection is a beta adrenergic blocker indicated for the short-term treatment of: Control of ventricular rate in supraventricular tachycardia including atrial fibrillation and atrial flutter and control of heart rate in noncompensatory sinus tachycardia ( 1.1 ) Control of perioperative tachycardia and hypertension ( 1.2 ) 1.1 Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia Esmolol Hydrochloride in Sodium Chloride 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 in Sodium Chloride Injection is also indicated in noncompensatory sinus tachycardia where, in the physician's judgment, the rapid heart rate requires specific intervention. Esmolol Hydrochloride in Sodium Chloride Injection is intended for short-term use. 1.2 Intraoperative and Postoperative Tachycardia and/or Hypertension Esmolol Hydrochloride in Sodium Chloride 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 in Sodium Chloride Injection to prevent such events is not recommended.

Administer intravenously ( 2.1 , 2.2 ) Titrate using ventricular rate or blood pressure at ≥4-minute intervals ( 2.1 , 2.2 ) Supraventricular tachycardia (SVT) or noncompensatory sinus tachycardia ( 2.1 ) Optional loading dose: 500 mcg per kg infused over one minute Then 50 mcg per kg per minute for the next 4 minutes Adjust dose as needed to a maximum of 200 mcg per kg per minute Additional loading doses may be administered Perioperative tachycardia and hypertension ( 2.2 ) Loading dose: 500 mcg per kg over 1 minute for gradual control (1 mg per kg over 30 seconds for immediate control) Then 50 mcg per kg per minute for gradual control (150 mcg per kg per min for immediate control) adjusted to a 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 in sodium chloride 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 Step Action 1 Optional loading dose (500 mcg per kg over 1 minute), then 50 mcg per kg per min for 4 min 2 Optional loading dose if necessary, then 100 mcg per kg per min for 4 min 3 Optional loading dose if necessary, then 150 mcg per kg per min for 4 min 4 If necessary, increase dose to 200 mcg per kg per min 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 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 in Sodium Chloride 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 in sodium chloride injection to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of esmolol hydrochloride in sodium chloride injection as follows: Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride in sodium chloride injection infusion rate by one-half (50%). 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 in sodium chloride injection infusion. 2.4 Directions for Use Esmolol hydrochloride in sodium chloride injection is available as a ready-to-infuse premixed solution in a single-dose flexible container bag. Esmolol hydrochloride in sodium chloride 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. Premixed Flexible Container Bag The medication port is to be used solely for withdrawing an initial bolus from the bag. Use aseptic technique when withdrawing the bolus dose. Do not add any additional medications to the bag. Figure 1: Two-Port Flexible Container Bag Figure 1

Esmolol hydrochloride 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). Severe sinus bradycardia ( 4 ) Heart block greater than first degree ( 4 ) Sick sinus syndrome ( 4 ) Decompensated heart failure ( 4 ) Cardiogenic shock ( 4 ) Coadministration of IV cardiodepressant calcium-channel antagonists (e.g., verapamil) in close proximity to esmolol hydrochloride ( 4 , 7 ) Pulmonary hypertension ( 4 ) Known hypersensitivity to esmolol ( 4 )

Most common adverse reactions (incidence >10%) are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Sagent Pharmaceuticals at 1-866-625-1618 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 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 ( 5.1 )]. 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. System Organ Class (SOC) Preferred MedDRA Term Frequency VASCULAR DISORDERS Hypotension* Asymptomatic hypotension Symptomatic hypotension (hyperhidrosis, dizziness) 25% 12% GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Infusion site reactions (inflammation and induration) 8% GASTROINTESTINAL DISORDERS Nausea 7% NERVOUS SYSTEM DISORDERS Dizziness 3% Somnolence 3% 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 (<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

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 function, 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. Digitalis glycosides: Risk of bradycardia ( 7 ) Anticholinesterases: Prolongs neuromuscular blockade ( 7 ) Antihypertensive agents: Risk of rebound hypertension ( 7 ) Sympathomimetic drugs: Dose adjustment needed ( 7 ) Vasoconstrictive and positive inotropic effect substances: Avoid concomitant use ( 7 )

16.2 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F). [See USP Controlled Room Temperature.] Protect from freezing. Avoid excessive heat. Discard unused portion. Once drug has been withdrawn from ready-to-infuse premixed flexible container bag, the bag should be used within 24 hours, with any unused portion discarded. Visually inspect the container. If the administration port protector is damaged, detached, or not present, discard container as solution path sterility may be impaired. Do not use plastic containers in series connections. Such use could result in an embolism due to residual air being drawn from the primary container before administration of the fluid from the secondary container is completed. Do not remove unit from overwrap until ready to use. Do not use if overwrap has been previously opened or damaged. The overwrap is a moisture barrier. The inner bag maintains sterility of the solution. Tear overwrap at notch and remove premixed bag. Some opacity of the plastic due to moisture absorption during the sterilization process may be observed. This is normal and does not affect the solution quality or safety. The opacity will diminish gradually. Caution: After removing the overwrap check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard container as sterility may be compromised. Use only if solution is clear colorless to light yellow and the container is undamaged. Preparation for intravenous administration: Use aseptic technique. Suspend premixed bag from eyelet support. Remove plastic protector from delivery port at bottom of bag. Attach administration set. Refer to directions for use. Sterile, Nonpyrogenic, Preservative-free, PVC-free, DEHP-free. The container closure is not made with natural rubber latex. Iso-Osmotic.