Brevibloc

1 INDICATIONS AND USAGE BREVIBLOC 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 BREVIBLOC (Esmolol Hydrochloride) 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. BREVIBLOC is also indicated in noncompensatory sinus tachycardia where, in the physician's judgment, the rapid heart rate requires specific intervention. BREVIBLOC is intended for short-term use. 1.2 Intraoperative and Postoperative Tachycardia and/or Hypertension BREVIBLOC (Esmolol Hydrochloride) 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 BREVIBLOC to prevent such events is not recommended.

2 DOSAGE AND ADMINISTRATION 2.1 Dosing for the Treatment of Supraventricular Tachycardia or Noncompensatory Sinus Tachycardia BREVIBLOC 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. 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 (250-300 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 BREVIBLOC 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 BREVIBLOC to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of BREVIBLOC as follows: Thirty minutes following the first dose of the alternative drug, reduce the BREVIBLOC 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 BREVIBLOC infusion. 2.4 Directions for Use BREVIBLOC injection is available in a pre-mixed bag and ready-to-use vial. BREVIBLOC 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. Ready-to-Use Vial The Ready-to-use Vial may be used to administer a loading dosage by hand-held syringe while the maintenance infusion is being prepared [see How Supplied/Storage and Handling (16.2)]. Compatibility with Commonly Used Intravenous Fluids BREVIBLOC was tested for compatibility with ten commonly used intravenous fluids at a final concentration of 10 mg esmolol hydrochloride per mL. BREVIBLOC 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 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 or 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 min infusion 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) Table1.jpg Figure1.jpg

4 CONTRAINDICATIONS BREVIBLOC (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 BREVIBLOC in close proximity (i.e., while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving BREVIBLOC 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 BREVIBLOC injection (4, 7) Pulmonary hypertension (4) Known hypersensitivity to esmolol (4)

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 mellitus: Increases the effect of hypoglycemic agents and masks hypoglycemic tachycardia (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 BREVIBLOC 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 BREVIBLOC 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 BREVIBLOC [see Contraindications (4)]. If severe bradycardia develops, reduce or stop BREVIBLOC. 5.3 Cardiac Failure Beta blockers, like BREVIBLOC 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 BREVIBLOC and start supportive therapy [see Overdosage (10)]. 5.4 Intraoperative and Postoperative Tachycardia and/or Hypertension Monitor vital signs closely and titrate BREVIBLOC slowly in the treatment of patients whose blood pressure is primarily driven by vasoconstriction associated with hypothermia. 5.5 Reactive Airways Disease Patients with reactive airways disease should, in general, not receive beta blockers. Because of its relative beta1 selectivity and titratability, titrate BREVIBLOC to the lowest possible effective dose. In the event of bronchospasm, stop the infusion immediately; a beta2 stimulating agent may be administered with appropriate monitoring of ventricular rates. 5.6 Use in Patients with Diabetes Mellitus and Hypoglycemia In patients with hypoglycemia, or diabetic patients (especially those with labile diabetes) who are receiving insulin or other hypoglycemic agents, beta blockers may mask tachycardia occurring with hypoglycemia, but other manifestations such as dizziness and sweating may not be masked. Concomitant use of beta blockers and antidiabetic agents can enhance the effect of antidiabetic agents (blood glucose-lowering). 5.7 Infusion Site Reactions Infusion site reactions have occurred with the use of BREVIBLOC 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 Patients with Pheochromocytoma If BREVIBLOC is used in the setting of pheochromocytoma, give it in combination with an alpha-blocker, and only after the alpha-blocker has been initiated. Administration of beta-blockers alone in the setting of pheochromocytoma has been associated with a paradoxical increase in blood pressure from the attenuation of beta-mediated vasodilation in skeletal muscle. 5.10 Use in Hypovolemic Patients In hypovolemic patients, BREVIBLOC injection can attenuate reflex tachycardia and increase the risk of hypotension. 5.11 Use in Patients with Peripheral Circulatory Disorders In patients with peripheral circulatory disorders (including Raynaud's disease or syndrome, and peripheral occlusive vascular disease), BREVIBLOC may aggravate peripheral circulatory disorders. 5.12 Abrupt Discontinuation of BREVIBLOC Injection Severe exacerbations of angina, myocardial infarction, and ventricular arrhythmias have been reported in patients with coronary artery disease upon abrupt discontinuation of beta blocker therapy. Observe patients for signs of myocardial ischemia when discontinuing BREVIBLOC. Heart rate increases moderately above pretreatment levels 30 minutes after BREVIBLOC discontinuation. 5.13 Hyperkalemia Beta blockers, including BREVIBLOC, have been associated with increases in serum potassium levels and hyperkalemia. The risk is increased in patients with risk factors such as renal impairment. Intravenous administration of beta blockers has been reported to cause potentially life-threatening hyperkalemia in hemodialysis patients. Monitor serum electrolytes during therapy with BREVIBLOC. 5.14 Use in Patients with Metabolic Acidosis Beta blockers, including BREVIBLOC, have been reported to cause hyperkalemic renal tubular acidosis. Acidosis in general may be associated with reduced cardiac contractility. 5.15 Use in Patients with Hyperthyroidism Beta-adrenergic blockade may mask certain chemical signs (e.g., tachycardia) of hyperthyroidism. Abrupt withdrawal of beta blockade might precipitate a thyroid storm; therefore, monitor patients for signs of thyrotoxicosis when withdrawing beta blocking therapy. 5.16 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions When using beta blockers, patients at risk of anaphylactic reactions may be more reactive to allergen exposure (accidental, diagnostic, or therapeutic). Patients using beta blockers may be unresponsive to the usual doses of epinephrine used to treat anaphylactic or anaphylactoid reactions [see Drug Interactions (7)].

7 DRUG INTERACTIONS Concomitant use of BREVIBLOC 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 BREVIBLOC'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 monoxide below.) BREVIBLOC 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 BREVIBLOC leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect BREVIBLOC pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease the heart rate. Concomitant use increases the risk of bradycardia. Anticholinesterases: BREVIBLOC 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 BREVIBLOC 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 BREVIBLOC. Vasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular resistance, do not use BREVIBLOC 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)

6 ADVERSE REACTIONS Most common adverse reactions (incidence >10%) are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension (6) To report SUSPECTED ADVERSE REACTIONS, contact Baxter Healthcare Corporation at 1-866-888-2472 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 BREVIBLOC (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 BREVIBLOC was presumably being used to control ventricular rate [see Warnings and Precautions (5.5)]. 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%) Table3 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

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. BREVIBLOC 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.