esmolol hydrochloride in sodium chloride

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/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.

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 min 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 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: 1. Thirty minutes following the first dose of the alternative drug, reduce the esmolol …

5 WARNINGS AND PRECAUTIONS • Risk of hypotension, bradycardia, and cardiac failure: Monitor for signs and symptoms of cardiovascular adverse effects. Reduce or discontinue use ( 5.1 , 5.2 , 5.3 , 5.10 ) • Risk of exacerbating reactive airway disease ( 5.5 ) • Diabetes: May mask symptoms of hypoglycemia and alter glucose levels; monitor ( 5.6 ) • Risk of unopposed alpha-agonism and severe hypertension in untreated pheochromocytoma ( 5.9 ) • Risk 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 in sodium chloride 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 in sodium chloride 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 in sodium chloride injection [see Contraindications (4) ] . If severe bradycardia develops, reduce or stop esmolol hydrochloride in sodium chloride injection. 5.3 Cardiac Failure Beta blockers, like esmolol hydrochloride in sodium chloride 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 in sodium chloride injection and start supportive therapy [see Overdosage (10) ] . 5.4 Intraoperative and Postoperative Tachycardia and/or Hypertension Monitor vital signs closely and titrate esmolol hydrochloride in sodium chloride 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 beta 1 selectivity and titratability, titrate esmolol hydrochloride in sodium chloride injection to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; a beta 2 stimulating agent may be administered with appropriate monitoring of ventricular rates. 5.6 Hypoglycemia Beta-blockers may prevent early warning signs of hypoglycemia, such as tachycardia, and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in patients with diabetes mellitus or children and patients who are fasting (i.e., surgery, not eating regularly, or are vomiting). If severe hypoglycemia occurs, patients should be instructed to seek emergency treatment. 5.7 Infusion Site Reactions Infusion site reactions have occurred with the use of esmolol hydrochloride in sodium chloride 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 a butterfly catheter. If a local infusion site reaction develops, use an alternative infusion site and avoid extravasation. 5.8 Use in Patients with Prinzmetal’s Angina Beta blockers may exacerbate anginal attacks in patients with Prinzmetal’s angina because of unopposed alpha receptor–mediated coronary artery vasoconstriction. Do not use nonselective beta blockers. 5.9 Use in Patie…

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 )

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 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 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 )

8.1 Pregnancy 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.

8.3 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.

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 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 (5.1) ] . 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 3 Clinical Trial Adverse Reactions (Frequency ≥3%) * Hypotension resolved during esmolol hydrochloride in sodium chloride 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