ESMOLOL HYDROCHLORIDE- esmolol hydrochloride_injection, solution

Esmolol hydrochloride is a beta 1 1 2 Clinical pharmacology studies in normal volunteers have confirmed the beta blocking activity of esmolol hydrochloride, showing reduction in heart rate at rest and during exercise, and attenuation of isoproterenol-induced increases in heart rate. Blood levels of esmolol hydrochloride 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 exhibits negligible pharmacological activity. 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.

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) 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. 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.

Administer intravenously (2. 2) Titrate using ventricular rate or blood pressure at >=4-minute intervals. 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) 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), 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. 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. 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. After patients achieve adequate control of the heart rate and a stable clinical status, transition to alternative antiarrhythmic drugs may be accomplished. Thirty minutes following the first dose of the alternative drug, reduce the esmolol hydrochloride infusion rate by one-half (50%). After administration of the second dose of the alternative drug, monitor the patient's response and if satisfactory control is maintained for the first hour, discontinue the esmolol hydrochloride infusion. 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. 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 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.

Most common adverse reactions (incidence >10%) are symptomatic hypotension (hyperhidrosis, dizziness) and asymptomatic hypotension (6) www. gov/medwatch. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The following adverse reaction rates are based on use of esmolol hydrochloride in clinical trials involving 369 patients with supraventricular tachycardia and over 600 intraoperative and postoperative patients enrolled in clinical trials. Most adverse effects observed in controlled clinical trial settings have been mild and transient. The most important and common adverse effect has been hypotension [see Warnings and Precautions (5. 1) [see Warnings and Precautions (5. 5) Table 3 Clinical Trial Adverse Reactions (Frequency >=3%) System Organ Class (SOC) Preferred MedDRA Term Frequency VASCULAR DISORDERS Hypotension* GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS Infusion site reactions 8% GASTROINTESTINAL DISORDERS Nausea 7% NERVOUS SYSTEM DISORDERS Dizziness 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%) 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.

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. 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. , verapamil) and esmolol hydrochloride in close proximity (i. , while cardiac effects from the other are still present); fatal cardiac arrests have occurred in patients receiving esmolol hydrochloride and intravenous verapamil. Pulmonary hypertension: May precipitate cardiorespiratory compromise. Hypersensitivity reactions, including anaphylaxis, to esmolol or any of the inactive ingredients of the product (cross-sensitivity between beta blockers is possible). Severe sinus bradycardia (4) Heart block greater than first degree (4) Sick sinus syndrome (4) Decompensated heart failure (4) Cardiogenic shock (4) Coadministration of IV cardiodepressant calcium-channel antagonists (e. verapamil) in close proximity to esmolol hydrochloride injection (4, 7) Pulmonary hypertension (4) Known hypersensitivity to esmolol (4).

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 should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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. 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, 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. The safety and effectiveness of esmolol hydrochloride in pediatric patients have not been established. Clinical studies of esmolol hydrochloride 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. No special precautions are necessary in patients with hepatic impairment because esmolol hydrochloride is metabolized by red-blood cell esterases [see Clinical Pharmacology (12) 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).

Concomitant use of esmolol hydrochloride with other drugs that can lower blood pressure, reduce myocardial contractility, or interfere with sinus node function or electrical impulse propagation in the myocardium can exaggerate esmolol hydrochloride’s effects on blood pressure, contractility, and impulse propagation. Severe interactions with such drugs can result in, for example, severe hypotension, cardiac failure, severe bradycardia, sinus pause, sinoatrial block, atrioventricular block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate increased withdrawal effects. (See clonidine, guanfacine, and moxonidine below. ) Esmolol hydrochloride should therefore be used only after careful individual assessment of the risks and expected benefits in patients receiving drugs that can cause these types of pharmacodynamic interactions, including but not limited to: Digitalis glycosides: Concomitant administration of digoxin and esmolol hydrochloride leads to an approximate 10% to 20% increase of digoxin blood levels at some time points. Digoxin does not affect esmolol hydrochloride pharmacokinetics. Both digoxin and beta blockers slow atrioventricular conduction and decrease heart rate. Concomitant use increases the risk of bradycardia. Anticholinesterases: Esmolol hydrochloride prolonged the duration of succinylcholine-induced neuromuscular blockade and moderately prolonged clinical duration and recovery index of mivacurium. Antihypertensive agents clonidine, guanfacine, or moxonidine: Beta blockers also increase the risk of clonidine-, guanfacine-, or moxonidine-withdrawal rebound hypertension. If, during concomitant use of a beta blocker, antihypertensive therapy needs to be interrupted or discontinued, discontinue the beta blocker first, and the discontinuation should be gradual. Calcium channel antagonists: In patients with depressed myocardial function, use of esmolol hydrochloride with cardiodepressant calcium channel antagonists (e. , verapamil) can lead to fatal cardiac arrests. Sympathomimetic drugs: Sympathomimetic drugs having beta-adrenergic agonist activity will counteract effects of esmolol hydrochloride. Vasoconstrictive and positive inotropic agents: Because of the risk of reducing cardiac contractility in presence of high systemic vascular resistance, do not use esmolol hydrochloride to control tachycardia in patients receiving drugs that are vasoconstrictive and have positive inotropic effects, such as epinephrine, norepinephrine, and dopamine. Digitalis glycosides: Risk of bradycardia (7) Anticholinesterases: Prolongs neuromuscular blockade (7) Antihypertensive agents: Risk of rebound hypertension (7) Sympathomimetic drugs: Dose adjustment needed (7) Vasoconstrictive and positive inotropic effect substances: Avoid concomitant use (7).

OVERDOSAGE
Overdoses of esmolol hydrochloride 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 (1 st nd rd 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. Because of its approximately 9-minute elimination half-life, the first step in the management of toxicity should be to discontinue the esmolol hydrochloride infusion. Then, based on the observed clinical effects, consider the following general measures. Bradycardia 2 Massive accidental overdoses of esmolol hydrochloride have resulted from dilution errors. Use of esmolol hydrochloride sodium chloride injection and esmolol hydrochloride sodium chloride injection double strength 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 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 resolved.
NONCLINICAL TOXICOLOGY
Because of its short term usage no carcinogenicity, mutagenicity, or reproductive performance studies have been conducted with esmolol.
CLINICAL STUDIES
Supraventricular Tachycardia

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