`
`
`
`
`
`
`
`HIGHLIGHTS OF PRESCRIBING INFORMATION
`These highlights do not include all the information needed to use
`
`BREVIBLOC safely and effectively. See full prescribing information for
`BREVIBLOC.
`BREVIBLOC (esmolol hydrochloride) injection, for intravenous use
`
`Initial U.S. Approval: 1986
`----------------------------INDICATIONS AND USAGE---------------------------
`
`BREVIBLOC 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)
`
`----------------------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)
`---------------------DOSAGE FORMS AND STRENGTHS----------------------
`
`
`
`Injection: 100 mg/10 mL (10 mg/mL) in 10 mL vial (3)
`
`
`
`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)
`
`
`
`
`
`
`
`
`
`
`-------------------------------CONTRAINDICATIONS------------------------------
`
`
` 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 (4, 7)
`
`
` Pulmonary hypertension (4)
`
` Known hypersensitivity to esmolol (4)
`
`
`-----------------------WARNINGS AND PRECAUTIONS------------------------
`
` Risk of hypotension, bradycardia, and cardiac failure: 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)
`------------------------------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.
`
`------------------------------DRUG INTERACTIONS-------------------------------
`
`
` 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)
`
`See 17 for PATIENT COUNSELING INFORMATION
`
`
`
`
`
`
`
`
`Revised: 12/2012
`
`FULL PRESCRIBING INFORMATION: CONTENTS*
`
`1
`INDICATIONS AND USAGE
`
`1.1 Supraventricular Tachycardia or Noncompensatory Sinus
`Tachycardia
`
`Intraoperative and Postoperative Tachycardia and Hypertension
`1.2
`
`
`2 DOSAGE AND ADMINISTRATION
`
`2.1 Dosing for the Treatment of Supraventricular Tachycardia or
`Noncompensatory Sinus Tachycardia
`
`Intraoperative and Postoperative Tachycardia and Hypertension
`2.2
`
`2.3 Transition from BREVIBLOC Therapy to Alternative Drugs
`
`
`2.4 Directions for Use
`
`3 DOSAGE FORMS AND STRENGTHS
`
`4 CONTRAINDICATIONS
`
`5 WARNINGS AND PRECAUTIONS
`
`5.1 Hypotension
`
`5.2 Bradycardia
`
`5.3 Cardiac Failure
`
`5.4
`Intraoperative and Postoperative Tachycardia and Hypertension
`
`5.5 Reactive Airways Disease
`
`5.6 Use in Patients with Diabetes Mellitus and Hypoglycemia
`
`5.7
`Infusion Site Reactions
`
`5.8 Use in Patients with Prinzmetal’s Angina
`
`
`5.9 Use in Patients with Pheochromocytoma
`
`5.10 Use in Hypovolemic Patients
`
`
`5.11 Use in Patients with Peripheral Circulatory Disorders
`
`5.12 Abrupt Discontinuation of BREVIBLOC
`
`5.13 Hyperkalemia
`
`5.14 Use in Patients with Metabolic Acidosis
`
`5.15 Use in Patients with Hyperthyroidism
`
`
`5.16 Use in Patients at Risk of Severe Acute Hypersensitivity Reactions
`
`
`
`
`
`Reference ID: 3228733
`
`
`6 ADVERSE REACTIONS
`
`6.1 Clinical Trials Experience
`
`6.2 Post-Marketing Experience
`
`
`7 DRUG INTERACTIONS
`
`
`8 USE IN SPECIFIC POPULATIONS
`
`
`8.1 Pregnancy
`
`
`8.2 Labor and Delivery
`
`
`8.3 Nursing Mothers
`
`
`8.4 Pediatric Use
`
`8.5 Geriatric Use
`
`8.6 Hepatic Impairment
`
`8.7 Renal Impairment
`
`
`10 OVERDOSAGE
`
`10.1 Signs and Symptoms of Overdose
`
`10.2 Treatment Recommendations
`
`10.3 Dilution Errors
`11 DESCRIPTION
`11.1 BREVIBLOC Dosage Forms
`12 CLINICAL PHARMACOLOGY
`
`12.1 Mechanism of Action
`12.2 Pharmacodynamics
`
`12.3 Pharmacokinetics
`
`
`13 NONCLINICAL TOXICOLOGY
`14 CLINICAL STUDIES
`16 HOW SUPPLIED/STORAGE AND HANDLING
`16.1 How Supplied
`16.2 Storage
`
`17 PATIENT COUNSELING INFORMATION
`
`*Sections or subsections omitted from the Full Prescribing Information are not
`
`listed
`
`
`
`

`

`
`
` FULL PRESCRIBING INFORMATION
`
`
`1 INDICATIONS AND USAGE
`
`
`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 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.
`
`Table 1 Step-Wise Dosing
`Step Action
` 
` 
`Optional loading dose (500 mcg per kg over 1 minute),
`1
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
`then 50 mcg per kg per min for 4 min
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
`Optional loading dose if necessary, then 100 mcg per kg per min for 4 min
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
`Optional loading dose if necessary, then 150 mcg per kg per min for 4 min
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
`If necessary increase dose to 200 mcg per kg per min
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
` 
`
`2
` 
`3
` 
`4
` 
`
`
`In the absence of loading doses, continuous infusion of a single concentration of esmolol reaches
`pharmacokinetic and pharmacodynamic steady-state in about 30 minutes.
`
`Reference ID: 3228733
`
`
`
`

`

`
`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 (250-300 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 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.
`
`Reference ID: 3228733
`
`
`
`

`

`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:
`
`
`1. Thirty minutes following the first dose of the alternative drug, reduce the BREVIBLOC
`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
`BREVIBLOC infusion.
`
`
`2.4 Directions for Use
`
`BREVIBLOC 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.
`
`Figure 2: Two-Port IntraVia 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)].
`
`
`
`Reference ID: 3228733
`
`

`

`
`
` 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
`
`
`3 DOSAGE FORMS AND STRENGTHS
`
`All BREVIBLOC dosage forms are iso-osmotic solutions of Esmolol Hydrochloride in Sodium
`
`Chloride.
`
`Table 1 BREVIBLOC Presentations
`Product Name
`BREVIBLOC
`
`PREMIXED
`INJECTION
`(Esmolol Hydrochloride)
`
`Total Dose
`Esmolol
`Hydrochloride
`Concentration
`Packaging
`
`2500 mg / 250 mL
`
`
`10 mg/mL
`
`250 mL Bag
`
`
`4 CONTRAINDICATIONS
`
`BREVIBLOC
`DOUBLE STRENGTH
`PREMIXED
`INJECTION
`(Esmolol Hydrochloride)
`2000 mg / 100 mL
`
`
`20 mg/mL
`
`100 mL Bag
`
`
`
`BREVIBLOC
`INJECTION
`(Esmolol
`Hydrochloride)
`
`100 mg / 10 mL
`
`10 mg/mL
`
`10 mL Vial
`
`BREVIBLOC (Esmolol Hydrochloride) is contraindicated in patients with:
`
`Reference ID: 3228733
`
`
`
`

`

`
` 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).
`
`
` 5 WARNINGS AND PRECAUTIONS
`
`
`
`
`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. 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. 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.
`
`
`
`Reference ID: 3228733
`
`

`

`
`5.3 Cardiac Failure
`
`Beta blockers, like BREVIBLOC, 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 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 rate.
`
`
`
`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. They include irritation,
`inflammation, and severe reactions (thrombophlebitis, necrosis, and blistering), in particular when
`associated with extravasation [see Adverse Reactions (6.1)]. 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.
`
`Reference ID: 3228733
`
`
`
`

`

`
`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 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
`
`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 pre-treatment 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 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.
`
`Reference ID: 3228733
`
`
`
`

`

`
`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)].
`
`
`
`6 ADVERSE REACTIONS
`
`
`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 (5.3)]. Deaths have been
`reported in post-marketing experience occurring during complex clinical states where
`BREVIBLOC was presumably being used simply to control ventricular rate [see Warnings and
`Precautions (5.5)].
`
`Table 2 Clinical Trial Adverse Reactions (Frequency ≥3%)
`Preferred MedDRA Term
`System Organ Class (SOC)
`
`VASCULAR DISORDERS
`Hypotension*
`Asymptomatic hypotension
`Symptomatic hypotension
`(hyperhidrosis, dizziness)
`
`Frequency
`
`25%
`
`12%
`
`8%
`
`7%
`
`GENERAL DISORDERS
`AND ADMINISTRATION
`SITE CONDITIONS
`GASTROINTESTINAL
`DISORDERS
`NERVOUS SYSTEM
`DISORDERS
`
`Infusion site reactions
`(inflammation and induration)
`
`Nausea
`
`3%
`Dizziness
`3%
`Somnolence
`* Hypotension resolved during BREVIBLOC (esmolol hydrochloride) infusion in 63% of
`patients. In 80% of the remaining patients, hypotension resolved within 30 minutes following
`discontinuation of infusion.
`
`
`Reference ID: 3228733
`
`
`
`

`

`
`
` 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
`
`
`7 DRUG INTERACTIONS
`
`Concomitant use of BREVIBLOC 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
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`block, and/or cardiac arrest. In addition, with some drugs, beta blockade may precipitate
`increased withdrawal effects. (See clonidine, guanfacine, and moxonidine 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 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 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
`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.
`
`
`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. BREVIBLOC should be used during pregnancy only if the
`potential benefit justifies the potential risk to the fetus.
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`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. BREVIBLOC 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
`
`BREVIBLOC, 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 BREVIBLOC in pediatric patients have not been established.
`
`
`8.5 Geriatric Use
`
`Clinical studies of BREVIBLOC 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 BREVIBLOC 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)].
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`
` 10 OVERDOSAGE
`
`
`10.1 Signs and Symptoms of Overdose
`
`Overdoses of BREVIBLOC (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 (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 BREVIBLOC 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 BREVIBLOC have resulted from dilution errors. Use of
`BREVIBLOC PREMIXED INJECTION and BREVIBLOC DOUBLE STRENGTH PREMIXED
`INJECTION may reduce the potential for dilution errors. Some of these overdoses have been
`
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`fatal while others resulted in permanent disability. Bolus doses in the range of 625 mg to
`2.5 g (12.5-50 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 BREVIBLOC resolved.
`
`
`11 DESCRIPTION
`
`BREVIBLOC (Esmolol Hydrochloride) is a beta adrenergic receptor blocker with a very short
`duration of action (elimination half-life is approximately 9 minutes). Esmolol Hydrochloride is:
`
`
`
`
`(±)-Methyl p-[2-hydroxy-3-(isopropylamino) propoxy] hydrocinnamate hydrochloride and
`has the following structure:
`
`
`
` Esmolol Hydrochloride has the empirical formula C16H26NO4Cl and a molecular weight of
`331.8. It has one asymmetric center and exists as an enantiomeric pair.
`
`
`
`
` Esmolol Hydrochloride 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 BREVIBLOC Dosage Forms
`
`All BREVIBLOC presentations are clear, colorless to light yellow, sterile, nonpyrogenic,
`iso-osmotic solutions of esmolol hydrochloride in sodium chloride. The formulations for
`BREVIBLOC PREMIXED INJECTION, BREVIBLOC DOUBLE STRENGTH PREMIXED
`INJECTION, and BREVIBLOC INJECTION are described in the table below:
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`Reference ID: 3228733