10 ML esmolol hydrochloride 10 MG/ML Injection [Brevibloc]

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

DOSAGE 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) 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 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 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 Injection Therapy to Alternative Drugs After patients achieve adequate control of the heart rate and a stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished. When transitioning from esmolol hydrochloride injection to alternative drugs, the physician should carefully consider the labeling instructions of the alternative drug selected and reduce the dosage of esmolol hydrochloride injection as follows: 1. Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride infusion rate by one-half (50%). 2. After administration of the second dose of the alternative drug, monitor the patient's response and if satisfactory control is maintained for the first hour, discontinue the esmolol hydrochloride infusion. 2.4 Directions for Use Esmolol hydrochloride injection is available in a pre-mixed bag and single-dose vial. Esmolol hydrochloride injection is not compatible with Sodium Bicarbonate (5%) solution (limited stability) or furosemide (precipitation). Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. 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 1: Two-Port Flexible Container Single-Dose Vial The Single-Dose Vial may be used to administer a loading dosage by hand-held syringe while the maintenance infusion is being prepared [see How Supplied/Storage and Handling (16.2) ] . Compatibility with Commonly Used Intravenous Fluids Esmolol hydrochloride injection was tested for compatibility with ten commonly used intravenous fluids at a final concentration of 10 mg esmolol hydrochloride per mL. Esmolol hydrochloride injection was found to be compatible with the following solutions and was stable for at least 24 hours at controlled room temperature or under refrigeration: Dextrose (5%) Injection, USP Dextrose (5%) in Lactated Ringer’s Injection Dextrose (5%) in Ringer’s Injection Dextrose (5%) and Sodium Chloride (0.45%) Injection, USP Dextrose (5%) and Sodium Chloride (0.9%) Injection, USP Lactated Ringer’s Injection, USP Potassium Chloride (40 mEq/liter) in Dextrose (5%) Injection, USP Sodium Chloride (0.45%) Injection, USP Sodium Chloride (0.9%) Injection, USP Figure 1: Two-Port Flexible Container

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 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 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 injection [see Contraindications ( 4 )]. If severe bradycardia develops, reduce or stop esmolol hydrochloride injection. 5.3 Cardiac Failure Beta blockers, like esmolol hydrochloride 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 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 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 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 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 esmolol hydrochloride injection 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, esmolol hydrochloride 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), esmolol hydrochloride injection may aggravate peripheral circulatory disorders. 5.12 Abrupt Discontinuation of Esmolol Hydrochloride 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 esmolol hydrochloride injection. Heart rate increases moderately above pretreatment levels 30 minutes after esmolol hydrochloride injection discontinuation. 5.13 Hyperkalemia Beta blockers, including esmolol hydrochloride injection, 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 esmolol hydrochloride injection. 5.14 Use in Patients with Metabolic Acidosis Beta blockers, including esmolol hydrochloride injection, 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 clinical 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 )].

CONTRAINDICATIONS Esmolol hydrochloride injection is contraindicated in patients with: • Severe sinus bradycardia: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2) ] . • Heart block greater than first degree: Second- or third-degree atrioventricular block may precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2) ] . • Sick sinus syndrome: May precipitate or worsen bradycardia resulting in cardiogenic shock and cardiac arrest [see Warnings and Precautions (5.2) ] . • Decompensated heart failure: May worsen heart failure. • Cardiogenic shock: May precipitate further cardiovascular collapse and cause cardiac arrest. • IV administration of cardiodepressant calcium-channel antagonists (e.g., verapamil) and esmolol hydrochloride 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 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 injection ( 4 , 7 ) • Pulmonary hypertension ( 4 ) • Known hypersensitivity to esmolol ( 4 )

CLINICAL PHARMACOLOGY 12.1 Mechanism of Action Esmolol hydrochloride 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 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.Esmolol hydrochloride 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 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 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 injection have been shown to correlate with extent of beta blockade. After termination of infusion, substantial recovery from beta blockade is observed in 10-20 minutes. The acid metabolite of esmolol exhibits negligible pharmacological activity. In human electrophysiology studies, esmolol hydrochloride 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 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 injection produced reductions in heart rate, rate pressure product and cardiac index which were also similar to those produced by propranolol, but esmolol hydrochloride 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 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 infusion, all of the hemodynamic parameters had returned to pretreatment levels. The relative cardioselectivity of esmolol hydrochloride injection was demonstrated in 10 mildly asthmatic patients. Infusions of esmolol hydrochloride 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 injection produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically significant, and esmolol hydrochloride injection 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 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 injection for dosages from 50-300 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 73-88% 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 hour 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 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 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 injection has been shown to be 55% bound to human plasma protein, while the acid metabolite is only 10% bound.