Esmolol hydrochloride in sodium chloride

6 ADVERSE REACTIONS Most common adverse reactions (incidence> 10%) are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX) 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 sodium chloride 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 (5.3) ]. Deaths have been reported in post-marketing experience occurring during complex clinical states where esmolol hydrochloride in sodium chloride injection was presumably being used simply to control ventricular rate [see Warnings and Precautions (5.5) ]. Table 2 Clinical Trial Adverse Reactions (Frequency ≥3%) System Organ Class (SOC) Preferred MedDRA Term Frequency VASCULAR DISORDERS Hypotension* Asymptomatic hypotension 25% Symptomatic hypotension 12% (hyperhidrosis, dizziness) GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Infusion site reactions (inflammation and induration) 8% GASTROINTESTINAL DISORDERS Nausea 7% NERVOUS SYSTEM DISORDERS Dizziness 3% Somnolence 3% * Hypotension resolved during esmolol hydrochloride in sodium chloride injection 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

4 CONTRAINDICATIONS • Esmolol hydrochloride in sodium chloride 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 sodium chloride 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 in sodium chloride injection 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 in sodium chloride injection ( 4 , 7 ) • Pulmonary hypertension ( 4 ) • Known hypersensitivity to esmolol ( 4 )

11 DESCRIPTION Esmolol Hydrochloride in Sodium Chloride Injection is a beta adrenergic receptor blocker with a very short duration of action (elimination half-life is approximately 9 minutes). Esmolol Hydrochloride, USP is: (±)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and has the following structure: • Esmolol Hydrochloride, USP 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, 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 17.0 for propranolol. 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 [10 mg/mL] [250 mL] and Esmolol Hydrochloride in Sodium Chloride Injection [20 mg/mL] [100 mL] are described in the table below: Table3 Esmolol hydrochloride in sodium chloride injectionFormulations Esmolol Hydrochloride in Sodium Chloride Injection [10 mg/mL] [250 mL] Esmolol Hydrochloride in Sodium Chloride Injection [20 mg/mL] [100 mL] Esmolol Hydrochloride, USP 10 mg/mL 20mg/mL Sodium Chloride, USP 5.9 mg/mL 4.1mg/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/mL 2.8mg/mL Glacial Acetic Acid, USP 0.546 mg/mL 0.546mg/mL Sodium Hydroxide Q.S. to adjust pH to4.5-5.5 Hydrochloric Acid Q.S. to adjust pH to4.5-5.5 Q.S. =Quantity sufficient The calculated osmolarity of Esmolol Hydrochloride in Sodium Chloride Injection [10 mg/mL] [250 mL] and Esmolol Hydrochloride in Sodium Chloride Injection [20 mg/mL] [100 mL] is 312 mOsmol/L. The 250 mL and 100 mL bags are non-latex, non-PVC IntraVia bags with dual PVC ports. The IntraVia bags are manufactured from a specially designed multilayer plastic (PL 2408). 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. structure

2 DOSAGE AND ADMINISTRATION • 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 ) o Optional loading dose: 500 mcg per kg infused over one minute o Then 50 mcg per kg per minute for the next 4 minutes o Adjust dose as needed to a maximum of 200 mcg per kg per minute o Additional loading doses may be administered • Perioperative tachycardia and hypertension ( 2.2 ) o Loading dose: 500 mcg per kg over 1 minute for gradual control (1 mg per kg over 30 seconds for immediate control) o Then 50 mcg per kg per minute for gradual control (150 mcg per kg per minute for immediate control) adjusted to a maximum of 200 (tachycardia) or 300 (hypertension) mcg per kg per minute ( 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 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 Figure 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 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: 1. Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride in sodium chloride injection 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 in sodium chloride injection infusion. 2.4 Directions for Use Esmolol hydrochloride in sodium chloride injection is available in a pre-mixed 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 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 2: Two-Port IntraVia Bag bag

1 INDICATIONS AND USAGE 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 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.

10 OVERDOSAGE 10.1 Signs and Symptoms of Overdose Overdoses of esmolol hydrochloride in sodium chloride 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. • Cardiac 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. • Central nervous system effects include respiratory depression, seizures, sleep and mood disturbances, fatigue, lethargy, and coma. • In 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 in sodium chloride injection infusion. Then, based on the observed clinical effects, consider the following general measures . Bradycardia : Consider intravenous administration of atropine or another anticholinergic drug or cardiac pacing. Cardiac Failure Consider intravenous administration of a 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 hypotension Consider intravenous administration of fluids or vasopressor agents such as dopamine or norepinephrine. Bronchospasm Consider intravenous administration of a beta2 stimulating agent or a theophylline derivative. 10.3 Dilution Errors Massive accidental overdoses of esmolol hydrochloride in sodium chloride injection have resulted from dilution errors. Use of Esmolol Hydrochloride in Sodium Chloride Injection [10 mg/mL] [250 mL] and Esmolol Hydrochloride in Sodium Chloride Injection [20 mg/mL] [100 mL] 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 g (12.5 to 50 mg/kg) have been fatal. Patients have recovered completely from overdoses as high as 1.75 g given over one minute or doses of 7.5 g 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 in sodium chloride injection resolved.

7 DRUG INTERACTIONS Concomitant use of esmolol hydrochloride in sodium chloride 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 in sodium chloride injection’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 in sodium chloride 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: • Digitalis glycosides: Concomitant administration of digoxin and esmolol hydrochloride in sodium chloride injection leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect esmolol hydrochloride in sodium chloride injection pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia. • Anticholinesterases: Esmolol hydrochloride in sodium chloride injection 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 clondidine-, 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 in sodium chloride injection 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 in sodium chloride injection. • 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 in sodium chloride injection 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 )

12 CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Esmolol hydrochloride in sodium chloride injection is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a 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 9 minutes. Esmolol hydrochloride in sodium chloride 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 in sodium chloride 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 in sodium chloride injection have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10 to 20 minutes. The acid metabolite of esmolol exihibits negligible pharmacological activity. In human electrophysiology studies, esmolol hydrochloride in sodium chloride injection produced effects typical of a beta blocker; a 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 in sodium chloride 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 in sodium chloride injection produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but esmolol hydrochloride in sodium chloride injection produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min of esmolol hydrochloride in sodium chloride 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 in sodium chloride injection infusion, all of the hemodynamic parameters had returned to pretreatment levels. The relative cardioselectivity of esmolol hydrochloride in sodium chloride injection was demonstrated in 10 mildly asthmatic patients. Infusions of esmolol hydrochloride in sodium chloride 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 in sodium chloride injection produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and esmolol hydrochloride was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at a dosage of 1 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 in sodium chloride 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 a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. Using an appropriate loading dose, steady-state blood levels of esmolol hydrochloride in sodium chloride injection for dosages from 50 to 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 to 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 a clearance approximately equivalent to the glomerular filtration rate. After a 4 hours 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 in sodium chloride 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 in sodium chloride injection for up to 6 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 in sodium chloride injection has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.

12.1 Mechanism of Action Esmolol hydrochloride in sodium chloride injection is a beta1-selective (cardioselective) adrenergic receptor blocking agent with rapid onset, a 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 9 minutes. Esmolol hydrochloride in sodium chloride 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 in sodium chloride 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 in sodium chloride injection have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10 to 20 minutes. The acid metabolite of esmolol exihibits negligible pharmacological activity. In human electrophysiology studies, esmolol hydrochloride in sodium chloride injection produced effects typical of a beta blocker; a 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 in sodium chloride 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 in sodium chloride injection produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but esmolol hydrochloride in sodium chloride injection produced a significantly larger fall in systolic blood pressure. In patients undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min of esmolol hydrochloride in sodium chloride 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 in sodium chloride injection infusion, all of the hemodynamic parameters had returned to pretreatment levels. The relative cardioselectivity of esmolol hydrochloride in sodium chloride injection was demonstrated in 10 mildly asthmatic patients. Infusions of esmolol hydrochloride in sodium chloride 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 in sodium chloride injection produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and esmolol hydrochloride was well tolerated by all patients. Six of the patients also received intravenous propranolol, and at a dosage of 1 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 in sodium chloride 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 a rapid distribution half-life of about 2 minutes and an elimination half-life of about 9 minutes. Using an appropriate loading dose, steady-state blood levels of esmolol hydrochloride in sodium chloride injection for dosages from 50 to 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 to 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 a clearance approximately equivalent to the glomerular filtration rate. After a 4 hours 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 in sodium chloride 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 in sodium chloride injection for up to 6 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 in sodium chloride injection has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.

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3 DOSAGE FORMS AND STRENGTHS All esmolol hydrochloride in sodium chloride injection dosage forms are iso-osmotic solutions of esmolol hydrochloride in sodium chloride. Table 1 Esmolol Hydrochloride in Sodium Chloride Injection Presentations Product Name Esmolol Hydrochloride in Sodium Chloride Injection [10 mg/mL] [250 mL] Esmolol Hydrochloride in Sodium Chloride Injection [20 mg/mL] [100 mL] Total Dose 2500 mg / 250 mL 2000 mg / 100 mL Esmolol Hydrochloride Concentration 10 mg/mL 20 mg/mL Packaging 250 mL Bag 100 mL Bag • Injection: 2500 mg/250 mL (10 mg/mL) in 250 mL Premixed Injection bag ( 3 ) • Injection: 2000 mg/100 mL (20 mg/mL) in 100 mL Double Strength Premixed Injection bag ( 3 )

esmolol hydrochloride in sodium chloride esmolol hydrochloride in sodium chloride ESMOLOL HYDROCHLORIDE ESMOLOL SODIUM CHLORIDE WATER SODIUM ACETATE ACETIC ACID SODIUM HYDROXIDE HYDROCHLORIC ACID esmolol hydrochloride in sodium chloride esmolol hydrochloride in sodium chloride ESMOLOL HYDROCHLORIDE ESMOLOL SODIUM CHLORIDE WATER SODIUM ACETATE ACETIC ACID SODIUM HYDROXIDE HYDROCHLORIC ACID

13 NONCLINICAL TOXICOLOGY Because of its short term usage no carcinogenicity, mutagenicity, or reproductive performance studies have been conducted with esmolol.

ANDA206608

Esmolol hydrochloride in sodium chloride

esmolol hydrochloride in sodium chloride

67457-657

HUMAN PRESCRIPTION DRUG

INTRAVENOUS

PACKAGE/LABEL PRINCIPAL DISPLAY PANEL NDC 67457-657-25 250 mL Esmolol Hydrochloride in Sodium Chloride Injection 2500 mg/250 mL (10 mg/mL) (Single-Dose Plastic Bag) Iso-Osmotic No Preservative Added Single Intravenous Use Only Rx only Mylan 250 mL Pouch

17 PATIENT COUNSELING INFORMATION Physicians should inform patients of the risks associated with esmolol hydrochloride in sodium chloride injection: The most common adverse reactions are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension. Manufactured for: Mylan Institutional LLC Rockford, IL 61103 U.S.A. Manufactured by: Mylan Laboratories Limited Bangalore, India DECEMBER 2017

14 CLINICAL STUDIES Supraventricular Tachycardia esmolol hydrochloride in sodium chloride injection were found to be more effective than placebo and about as effective as propranolol, 3 to 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 to 70% of the patients treated with esmolol hydrochloride in sodium chloride injection developed either a 20% reduction in heart rate, a 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 a dosage of 200 mcg/kg/min or less. The average effective dosage of esmolol hydrochloride in sodium chloride 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 in sodium chloride 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 to 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 in sodium chloride injection (53%) than with propranolol (17%). The hypotension was rapidly reversible with decreased infusion rate or after discontinuation of therapy with esmolol hydrochloride in sodium chloride injection. For both esmolol hydrochloride in sodium chloride injection and propranolol, hypotension was reported less frequently in patients receiving concomitant digoxin.

8.5 Geriatric Use Clinical studies of esmolol hydrochloride in sodium chloride 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.

8.2 Labor and Delivery Although there are no adequate and well-controlled studies in pregnant women, use of esmolol 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 in sodium chloride 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 in sodium chloride injection, a 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 in sodium chloride injection in pediatric patients have not been established.

8.1 Pregnancy Pregnancy Category C. Esmolol hydrochloride has been shown to produce increased fetal resorptions with minimal maternal toxicity in rabbits when given in doses approximately 8 times the maximum human maintenance dose (300 mcg/kg/min). There are no adequate and well-controlled studies in pregnant women. Esmolol hydrochloride in sodium chloride 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) 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 a 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 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C. Esmolol hydrochloride has been shown to produce increased fetal resorptions with minimal maternal toxicity in rabbits when given in doses approximately 8 times the maximum human maintenance dose (300 mcg/kg/min). There are no adequate and well-controlled studies in pregnant women. Esmolol hydrochloride in sodium chloride 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) 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 a 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 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 in sodium chloride 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 in sodium chloride injection, a 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 in sodium chloride injection in pediatric patients have not been established. 8.5 Geriatric Use Clinical studies of esmolol hydrochloride in sodium chloride 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 in sodium chloride injection is metabolized by red-blood cell esterases [see Clinical Pharmacology (12.3) ]. 8.7 Renal Impairment No dosage adjustment is required for esmolol in patients with renal impairment receiving a maintenance infusion of esmolol 150 mcg/kg for 4 hours. There is no information on the tolerability of maintenance infusions of esmolol using rates in excess of 150 mcg/kg or maintained longer than 4 hours [see Clinical Pharmacology (12.3) ].

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Esmolol Hydrochloride in Sodium Chloride Injection 2500 mg/250 mL (10 mg/mL) (Single-dose Plastic Bag) • NDC 67457-657-25 Esmolol Hydrochloride in Sodium Chloride Injection 2000 mg/100 mL (20 mg/mL) (Single-dose Plastic Bag) • NDC 67457-658-10 16.2 Storage Store at 25°C (77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Protect from freezing. Avoid excessive heat. Each bag contains no preservative. Once drug has been withdrawn from ready-to-use bag, the bag should be used within 24 hours, with any unused portion discarded. 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. Check for minute leaks by squeezing the inner bag firmly. If leaks are found, discard solution, as sterility may be impaired. Do not use unless the solution is clear (colorless to light yellow) and the seal is intact. 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 complete directions accompanying set.