BREVIBLOC (Brand for ESMOLOL HCL)

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Esmolol is clear and colorless to light yellow.
Intravenous Administration
-Esmolol is available as a premixed bag and ready-to-use vial.
-Only use the medication port of the premixed bag for withdrawing an initial bolus; do not add any additional medications to the bag. Alternatively, the ready-to-use vial can be used to administer a loading dose by hand-held syringe.
-Avoid infusions into small veins or through a butterfly catheter.
-Esmolol is NOT compatible with sodium bicarbonate or furosemide.
-Esmolol is compatible with the following solutions at a final concentration of 10 mg/mL and stable for at least 24 hours: 5% Dextrose Injection, 5% Dextrose and Lactated Ringer's Injection, 5% Dextrose and Ringer's Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, Lactated Ringer's Injection, 5% Dextrose Injection with potassium chloride 40 mEq/L, 0.45% Sodium Chloride Injection, and 0.9% Sodium Chloride Injection.
-Storage: Once drug has been withdrawn from bag, use the bag within 24 hours.

Loading dose
-Administer loading dose over 10 seconds to 2 minutes.

Continuous IV Infusion
-Infusions lasting longer than 48 hours have not been evaluated.

Most adverse reactions associated with esmolol are mild and transient; after discontinuation, substantial recovery from beta-blockade is observed in 10 to 20 minutes.

Hypotension can occur at any dose but is dose-related; monitor patients closely. In case of an unacceptable drop in blood pressure, reduce or discontinue esmolol. Hypotension was reported in 8% of pediatric patients (n = 118, neonates to 6 years) receiving esmolol for postoperative hypertension. In adult clinical trials, symptomatic (hyperhidrosis, dizziness) and asymptomatic hypotension were reported in 12% and 25% of patients, respectively. Hypotension resolved during esmolol infusion in 63% of patients; in 80% of the remaining patients, hypotension resolved within 30 minutes of drug discontinuation. Dizziness not related to hypotension occurred in 3% of adults.

Bradycardia, including sinus pause, AV block, severe bradycardia, and cardiac arrest, has occurred with esmolol use. Deaths have been reported in postmarketing experience during complex clinical states where esmolol was presumably being used simply to control ventricular rate. Bradycardia was reported in 1% of pediatric patients (n = 118, neonates to 6 years) receiving esmolol for postoperative hypertension. Monitor heart rate and rhythm in patients receiving esmolol; if severe bradycardia develops, reduce or discontinue esmolol. The negative inotropic and chronotropic effects of esmolol can exacerbate heart failure. Discontinue esmolol at the first sign or symptom of impending heart failure and start supportive therapy. Pallor and flushing (less than 1%) and peripheral ischemia (1%) were reported in adult clinical trials. Coronary arteriospasm has been reported with postmarketing use.

Nausea (7%) and vomiting (1%) were reported during adult clinical trials for esmolol; dyspepsia, constipation, xerostomia, and abdominal pain were also reported in less than 1% of adult patients.

Non-selective beta-blockers may inhibit catecholamine-induced glycogenolysis, gluconeogenesis, and lipolysis, predisposing to hypoglycemia. Additionally, beta-blockers can mask signs of hypoglycemia (e.g., tachycardia) and increase the risk for severe or prolonged hypoglycemia at any time during treatment. Persons should be instructed to seek emergency treatment if severe hypoglycemia occurs. Beta-blockers can also occasionally cause hyperglycemia. This is thought to be due to blockade of beta-2-receptors on pancreatic islet cells, which inhibit insulin secretion. Monitor blood glucose concentrations closely if a beta-blocker is used in a person with diabetes mellitus. In addition to acute blood glucose effects, beta-blockers have been shown to increase the risk of developing diabetes mellitus in adult hypertensive patients. The risk in pediatric patients is undefined.

Injection site reaction, including irritation, inflammation, thrombo-phlebitis, skin necrosis, and blistering, has occurred with esmolol use. Severe reactions are usually associated with extravasation. Use an alternative infusion site and avoid extravasation if a local infusion site reaction develops. Injection site reaction was reported in 1% of pediatric patients (n = 118, neonate to 6 years) receiving esmolol for postoperative hypertension. In adult trials, infusion site inflammation and induration were reported in 8% of patients.

Wheezing was reported in 3% of pediatric patients (n = 118, neonate to 6 years) receiving esmolol for postoperative hypertension. Titrate esmolol 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.

Dizziness (3%), drowsiness (3%), headache (2%), and confusion and agitation (2%) were reported in adult patients during esmolol clinical trials. Paresthesias, syncope, anxiety, depression, abnormal thinking, speech disorder, and lightheadedness were reported in less than 1% of adult patients. Seizures were also reported in less than 1% of patients, including 1 death.

Urinary retention was reported in less than 1% of adult patients during esmolol clinical trials.

Angioedema, urticaria, and psoriasis have been reported with postmarketing use of esmolol. While taking beta-blockers, patients may be unresponsive to the usual doses of epinephrine used to treat an allergic reaction.

Esmolol has been associated with increases in serum potassium concentrations and hyperkalemia; monitor serum electrolytes during therapy with esmolol.

In general, do not use beta-blockers in patients with reactive airway disease (e.g., asthma, chronic lung disease (CLD), bronchitis). Because of its relative beta1-selectivity and titratability, titrate esmolol 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.

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. Heart rate increases moderately above pretreatment levels 30 minutes after esmolol discontinuation.

Esmolol is contraindicated in patients with severe bradycardia, second- or third-degree AV block, sick sinus syndrome, and cardiogenic shock due to precipitation or worsening of bradycardia in these conditions, which may result in cardiogenic shock and/or cardiac arrest. Patients with first-degree AV block, sinus node dysfunction, or conduction disorders may be at increased risk of sinus pause, heart block, severe bradycardia, and cardiac arrest. Monitor heart rate and rhythm in patients receiving esmolol; if severe bradycardia develops, reduce or discontinue esmolol. Esmolol is also contraindicated in patients with decompensated heart failure and pulmonary hypertension. The negative inotropic and chronotropic effects of esmolol can exacerbate heart failure and precipitate cardiorespiratory compromise. Discontinue esmolol at the first sign or symptom of impending heart failure and start supportive therapy.

Beta-blockers may exacerbate anginal attacks in patients with vasospastic angina (Prinzmental's angina) because of unopposed alpha receptor-mediated coronary artery vasoconstriction. Do not use nonselective beta-blockers.

Esmolol may aggravate peripheral circulatory disorders, including Raynaud's phenomenon and peripheral vascular disease.

Non-selective beta-blockers may inhibit catecholamine-induced glycogenolysis, gluconeogenesis, and lipolysis, predisposing to hypoglycemia. Additionally, beta-blockers can mask signs of hypoglycemia (e.g., tachycardia) and increase the risk for severe or prolonged hypoglycemia at any time during treatment, especially in persons with diabetes mellitus or children and persons who are fasting (i.e., surgery, not eating regularly, or are vomiting). Persons should be instructed to seek emergency treatment if severe hypoglycemia occurs. Beta-blockers can also occasionally cause hyperglycemia. This is thought to be due to blockade of beta-2-receptors on pancreatic islet cells, which inhibit insulin secretion. Monitor blood glucose concentrations closely if a beta-blocker is used in a person with diabetes mellitus.

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.

Beta-blockers, including esmolol, have been associated with increases in serum potassium concentrations 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 patients with renal failure requiring dialysis. Monitor serum electrolytes during therapy with esmolol.

Avoid extravasation of esmolol. Do not administer esmolol into small veins or through a butterfly catheter. Use an alternative infusion site if a local infusion site reaction develops.

Esmolol is contraindicated in patients with hypersensitivity to the drug or any of the inactive ingredients of the product. Cross-sensitivity between beta-blockers (beta-blocker hypersensitivity) may occur. While taking beta-blockers, patients with a history of severe anaphylactic reaction to a variety of allergens may be more reactive to repeated challenge (accidental, diagnostic, or therapeutic). These patients may also be unresponsive to the usual doses of epinephrine used to treat the allergic reaction.

In patients with hypovolemia, esmolol can attenuate reflex tachycardia and increase the risk of hypotension. Hypotension can occur at any dose but is dose-related. Patients with hemodynamic compromise or on interacting medications are at particular risk. For control of ventricular heart rate, maintenance doses of more than 200 mcg/kg/minute are not recommended. Monitor patients closely, especially if pretreatment blood pressure is low. In case of an unacceptable drop in blood pressure, reduce or discontinue esmolol. Decrease of dose or termination of infusion reverses hypotension, usually within 30 minutes.

If esmolol is used in the setting of pheochromocytoma, administer 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.

Monitor vital signs closely and titrate esmolol slowly in intraoperative or postoperative patients whose blood pressure is primarily driven by vasoconstriction associated with hypothermia.

Description: Esmolol is an intravenous beta-blocker. Because of its rapid onset and short duration, it is useful for acute control of hypertension or certain supraventricular arrhythmias. The American Academy of Pediatrics considers esmolol useful for severely hypertensive patients with life-threatening symptoms. Doses of esmolol required to control heart rate and blood pressure in pediatric patients appear to be higher than those used in adult patients. Esmolol is generally well-tolerated with mild and transient adverse reactions. Pharmacodynamic effects such as excessive hypotension are rapidly reversible upon titration or discontinuation. Although not FDA-approved, esmolol has been used in pediatric patients as young as neonates.

For the treatment of supraventricular tachycardia (SVT)*:
Intravenous dosage:
Infants, Children, and Adolescents: 100 to 500 mcg/kg IV, then 50 to 500 mcg/kg/minute continuous IV infusion. Higher loading doses (up to 1,000 mcg/kg) with infusions up to 1,000 mcg/kg/minute have been used.

For the short-term treatment of postoperative hypertension*:
Continuous Intravenous Infusion dosage:
Neonates 0 to 7 days: 50 mcg/kg/minute continuous IV infusion, initially. Titrate by 25 to 50 mcg/kg/minute every 20 minutes until goal blood pressure is attained. Max: 1,000 mcg/kg/minute. Higher doses may be required after repair of coarctation of the aorta vs. other congenital defect surgeries. In a blinded, randomized, dose-ranging study (n = 118, 26 neonates), 125 to 500 mcg/kg IV, then 125 to 500 mcg/kg/minute continuous IV infusion was used to effectively control hypertension after coarctation repair. Dosing requirements were significantly higher in infants and children undergoing coarctation repair compared to those with other congenital heart defects (830 mcg/kg/minute vs. 570 mcg/kg/minute, p = 0.01).
Neonates 8 to 29 days: 75 mcg/kg/minute continuous IV infusion, initially. Titrate by 50 mcg/kg/minute every 20 minutes until goal blood pressure is attained. Max: 1,000 mcg/kg/minute. Higher doses may be required after repair of coarctation of the aorta vs. other congenital defect surgeries. In a blinded, randomized, dose-ranging study (n = 118, 26 neonates), 125 to 500 mcg/kg IV, then 125 to 500 mcg/kg/minute continuous IV infusion was used to effectively control hypertension after coarctation repair. Dosing requirements were significantly higher in infants and children undergoing coarctation repair compared to those with other congenital heart defects (830 mcg/kg/minute vs. 570 mcg/kg/minute, p = 0.01).
Infants: 125 to 500 mcg/kg IV, then 50 to 500 mcg/kg/minute continuous IV infusion, initially. Titrate by 50 mcg/kg/minute every 10 minutes until goal blood pressure is attained. Max: 1,000 mcg/kg/minute. In a single study, dosing requirements were significantly higher in patients undergoing coarctation repair compared those with other congenital heart defects (830 mcg/kg/minute vs. 570 mcg/kg/minute, p = 0.01).
Children and Adolescents: 125 to 500 mcg/kg IV, then 50 to 500 mcg/kg/minute continuous IV infusion, initially. Titrate by 50 to 100 mcg/kg/minute every 10 minutes until goal blood pressure is attained. Max: 1,000 mcg/kg/minute. In a single study, dosing requirements were significantly higher in patients undergoing coarctation repair compared to those with other congenital heart defects (830 mcg/kg/minute vs. 570 mcg/kg/minute, p = 0.01).

For the treatment of hypertensive urgency* or hypertensive emergency*:
Continuous Intravenous Infusion dosage:
Children and Adolescents: 100 to 500 mcg/kg IV, then 25 to 100 mcg/kg/minute continuous IV infusion, initially. Titrate dose every 10 to 15 minutes until goal blood pressure is attained. Usual dose: 50 to 500 mcg/kg/minute. Max: 1,000 mcg/kg/minute. A second loading dose may be necessary.

For the treatment of thyrotoxicosis*:
Intravenous dosage:
Neonates: 100 to 500 mcg/kg IV, then 25 to 100 mcg/kg/minute continuous IV infusion.
Infants, Children, and Adolescents: 100 to 500 mcg/kg IV, then 25 to 100 mcg/kg/minute continuous IV infusion.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, 500 mcg/kg/dose IV load and 1,000 mcg/kg/minute continuous IV infusion have been used.
-Infants
Safety and efficacy have not been established; however, 1,000 mcg/kg/dose IV load and 1,000 mcg/kg/minute continuous IV infusion have been used.
-Children
Safety and efficacy have not been established; however, 1,000 mcg/kg/dose IV load and 1,000 mcg/kg/minute continuous IV infusion have been used.
-Adolescents
Safety and efficacy have not been established; however, 1,000 mcg/kg/dose IV load and 1,000 mcg/kg/minute continuous IV infusion have been used.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
Specific guidelines for dosage adjustments in renal impairment in pediatric patients are not available. No dosage adjustment is required in adults with renal impairment receiving 150 mcg/kg/minute continuous IV infusion for 4 hours; however, there is no information on tolerability at higher doses or longer durations.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Esmolol is a beta1-selective adrenergic receptor blocking agent. It inhibits the beta1 receptors located chiefly in cardiac muscle; however, this preferential effect is not absolute, and at higher doses, it begins to inhibit beta2 receptors located in the bronchial and vascular musculature. Esmolol produces effects typical of a beta-blocker, including 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. Esmolol has no significant intrinsic sympathomimetic or membrane-stabilizing activity at therapeutic dosages.

Pharmacokinetics: Esmolol is administered intravenously. It is 55% bound to plasma protein. Esmolol is rapidly metabolized by hydrolysis of the ester linkage, primarily by esterases in the cytosol of red blood cells, to the corresponding free acid and methanol. The acid metabolite has negligible pharmacologic activity. Total body clearance is approximately 20 L/kg/hour in adults, which is greater than cardiac output; thus, metabolism is not limited by the rate of blood flow to metabolizing tissues or affected by hepatic or renal flow. 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% to 88% of the dosage. The elimination half-life of esmolol after intravenous infusion is approximately 9 minutes.

Affected cytochrome P450 isoenzymes and drug transporters: none


-Route-Specific Pharmacokinetics
Intravenous Route
Onset of action after IV injection is extremely rapid, with steady-state concentrations achieved within 5 minutes after a loading dose or within 30 minutes in the absence of a loading dose. Steady-state esmolol concentrations are proportional to the infusion rate and decrease rapidly after discontinuation, with substantial recovery from beta-blockade within 10 to 20 minutes.


-Special Populations
Pediatrics
Neonates and Infants
Arterial plasma concentrations of esmolol were significantly lower in neonates and infants (n = 64) compared to children receiving esmolol for postoperative blood pressure control. Esmolol clearance was also higher in neonates and infants compared to children (281 mL/kg/minute vs. 126 mL/kg/minute); however, due to the high degree of interpatient variability, correlation of clearance with age was not possible. The time to steady-state (21 minutes) and elimination half-life (4.8 minutes) did not vary with age.

Children and Adolescents
The mean clearance and elimination half-life of esmolol were 119 mL/kg/minute and 6.9 minutes, respectively, in 25 patients (3 to 16 years) with supraventricular tachycardia. Clearance was not related to age or weight and was similar to values reported in adult patients.

Renal Impairment
After a 4-hour infusion, plasma concentrations of esmolol are similar in patients with normal renal function and those with end-stage renal disease (ESRD) on dialysis; however, peak concentrations of the acid metabolite are doubled. The acid metabolite half-life is increased about 12-fold to 48 hours in patients with ESRD.