BREVIBLOC PREMIXED INJECTION
`
`(Esmolol Hydrochloride)
`
`2,500 mg/250 mL (10 mg/mL) Ready-to-use Bags
`
`250 mL Bags
`
`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride
`
`For Intravenous Use
`
`Can be used for direct intravenous use.
`
`Esmolol Hydrochloride concentration = 10 milligrams/mL (10,000 micrograms/mL)
`
`Single Patient Use Only
`
`No Preservatives Added
`
`BREVIBLOC DOUBLE STRENGTH PREMIXED
`INJECTION
`
`(Esmolol Hydrochloride)
`
`2,000 mg/100 mL (20 mg/mL) Ready-to-use Bags
`
`100 mL Bags
`
`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride
`
`For Intravenous Use
`
`Can be used for direct intravenous use.
`
`Esmolol Hydrochloride concentration = 20 milligrams/mL (20,000 micrograms/mL)
`
`Single Patient Use Only
`
`No Preservatives Added
`
`BREVIBLOC INJECTION
`
`1
`
`

`

`(Esmolol Hydrochloride)
`
`100 mg/10 mL (10 mg/mL) Ready-to-use Vials
`
`10 mL Vials
`
`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride
`
`For Intravenous Use
`
`Can be used for direct intravenous use.
`
`Esmolol Hydrochloride concentration = 10 milligrams/mL (10,000 micrograms/mL)
`
`Single Patient Use Only
`
`No Preservatives Added
`
`BREVIBLOC DOUBLE STRENGTH INJECTION
`
`(Esmolol Hydrochloride)
`
`100 mg/5 mL (20 mg/mL) Ready-to-use Vials
`
`5 mL Vials
`
`Iso-Osmotic Solution of Esmolol Hydrochloride in Sodium Chloride
`
`For Intravenous Use
`
`Can be used for direct intravenous use.
`
`Esmolol Hydrochloride concentration = 20 milligrams/mL (20,000 micrograms/mL)
`
`Single Patient Use Only
`
`No Preservatives Added
`
`Rx only
`
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`

`DESCRIPTION
`
`BREVIBLOC (Esmolol Hydrochloride) is a beta1-selective (cardioselective) adrenergic
`receptor blocking agent 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.
`
`Brevibloc Premixed Injection
`
`BREVIBLOC PREMIXED INJECTION is a clear, colorless to light yellow, sterile,
`nonpyrogenic, iso-osmotic solution of esmolol hydrochloride in sodium chloride.
`
`2500 mg, 250 mL Single Use Premixed Bag – Each mL contains 10 mg Esmolol
`Hydrochloride, 5.9 mg Sodium Chloride, USP and Water for Injection, USP; buffered
`with 2.8 mg Sodium Acetate Trihydrate, USP and 0.546 mg Glacial Acetic Acid,
`USP. Sodium Hydroxide and/or Hydrochloric Acid added, as necessary, to adjust pH
`to 5.0 (4.5-5.5). The calculated osmolarity is 312 mOsmol/L. The 250 mL bag is a
`non-latex, non-PVC IntraVia bag with dual PVC ports. The IntraVia bag is
`manufactured from a specially designed multilayer plastic (PL 2408). Solutions in
`contact with the plastic container leach out certain chemical compounds from the
`plastic in very small amounts; however, biological testing was supportive of the
`safety of the plastic container materials. See DOSAGE AND ADMINISTRATION,
`Directions for Use of the Premixed Bag for additional information.
`
`2000 mg, 100 mL Single Use Premixed Bag DOUBLE STRENGTH – Each mL
`contains 20 mg Esmolol Hydrochloride, 4.1 mg Sodium Chloride, USP and Water for
`Injection, USP; buffered with 2.8 mg Sodium Acetate Trihydrate, USP and 0.546 mg
`Glacial Acetic Acid, USP. Sodium Hydroxide and/or Hydrochloric Acid added, as
`
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`

`necessary, to adjust pH to 5.0 (4.5-5.5). The calculated osmolarity is 312 mOsmol/L.
`The 100 mL bag is a non-latex, non-PVC IntraVia bag with dual PVC ports. The
`IntraVia bag is manufactured from a specially designed multilayer plastic (PL 2408).
`Solutions in contact with the plastic container leach out certain chemical compounds
`from the plastic in very small amounts; however, biological testing was supportive of
`the safety of the plastic container materials. See DOSAGE AND
`ADMINISTRATION, Directions for Use of the Premixed Bag for
`additional information.
`
`Brevibloc Injection
`
`BREVIBLOC INJECTION is a clear, colorless to light yellow, sterile, nonpyrogenic,
`iso-osmotic solution of esmolol hydrochloride in sodium chloride.
`
`100 mg, 10 mL Single Dose Vial – Each mL contains 10 mg Esmolol Hydrochloride,
`5.9 mg Sodium Chloride, USP and Water for Injection, USP; buffered with 2.8 mg
`Sodium Acetate Trihydrate, USP and 0.546 mg Glacial Acetic Acid, USP. Sodium
`Hydroxide and/or Hydrochloric Acid added, as necessary to adjust pH
`to 5.0 (4.5-5.5).
`
`100 mg, 5 mL DOUBLE STRENGTH Single Dose Vial – Each mL contains 20 mg
`Esmolol Hydrochloride, 4.1 mg Sodium Chloride, USP and Water for Injection, USP;
`buffered with 2.8 mg Sodium Acetate Trihydrate, USP and 0.546 mg Glacial Acetic
`Acid, USP. Sodium Hydroxide and/or Hydrochloric Acid added, as necessary to
`adjust pH to 5.0 (4.5-5.5).
`
`CLINICAL PHARMACOLOGY
`
`BREVIBLOC (Esmolol Hydrochloride) 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.
`BREVIBLOC 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.
`
`Pharmacokinetics and Metabolism
`
`BREVIBLOC (Esmolol Hydrochloride) is rapidly metabolized by hydrolysis of the ester
`linkage, chiefly by the esterases in the cytosol of red blood cells and not by plasma
`
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`

`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 BREVIBLOC is not limited by the rate of blood flow to metabolizing
`tissues such as the liver or affected by hepatic or renal blood flow. BREVIBLOC 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 BREVIBLOC for dosages
`from 50-300 mcg/kg/min (0.05-0.3 mg/kg/min) are obtained within five minutes.
`(Steady-state is reached in about 30 minutes without the loading dose.) Steady-state
`blood levels of BREVIBLOC 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 BREVIBLOC 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 BREVIBLOC, less than 2%
`of the drug is excreted unchanged in the urine. Within 24 hours of the end of infusion,
`approximately 73-88% of the dosage has been accounted for in the urine as the acid
`metabolite of BREVIBLOC.
`
`Metabolism of BREVIBLOC results in the formation of the corresponding free acid and
`methanol. The acid metabolite has been shown in animals to have about 1/1500th the
`activity of esmolol 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. Excretion of the acid metabolite is significantly decreased in patients with
`renal disease, with the elimination half-life increased to about ten-fold that of normals,
`and plasma levels considerably elevated.
`
`Methanol blood levels, monitored in subjects receiving BREVIBLOC for up to 6 hours at
`300 mcg/kg/min (0.3 mg/kg/min) and 24 hours at 150 mcg/kg/min (0.15 mg/kg/min),
`approximated endogenous levels and were less than 2% of levels usually associated with
`methanol toxicity.
`
`BREVIBLOC has been shown to be 55% bound to human plasma protein, while the acid
`metabolite is only 10% bound.
`
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`Pharmacodynamics
`
`Clinical pharmacology studies in normal volunteers have confirmed the beta blocking
`activity of BREVIBLOC (Esmolol Hydrochloride), showing reduction in heart rate at rest
`and during exercise, and attenuation of isoproterenol-induced increases in heart rate.
`Blood levels of BREVIBLOC 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.
`
`In human electrophysiology studies, BREVIBLOC 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, BREVIBLOC, at dosages of
`200 mcg/kg/min (0.2 mg/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, BREVIBLOC produced reductions in heart rate,
`rate pressure product and cardiac index which were also similar to those produced by
`propranolol, but produced a significantly larger fall in systolic blood pressure. In patients
`undergoing cardiac catheterization, the maximum therapeutic dose of 300 mcg/kg/min
`(0.3 mg/kg/min) of BREVIBLOC 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 thirty minutes after the discontinuation of
`BREVIBLOC infusion, all of the hemodynamic parameters had returned to
`pretreatment levels.
`
`The relative cardioselectivity of BREVIBLOC was demonstrated in 10 mildly asthmatic
`patients. Infusions of BREVIBLOC [100, 200 and 300 mcg/kg/min (0.1, 0.2 and
`0.3 mg/kg/min)] produced no significant increases in specific airway resistance compared
`to placebo. At 300 mcg/kg/min (0.3 mg/kg/min), BREVIBLOC produced slightly
`enhanced bronchomotor sensitivity to dry air stimulus. These effects were not clinically
`significant, and BREVIBLOC 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
`
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`BREVIBLOC for treatment of supraventricular tachycardia (51 patients) or in
`perioperative settings (32 patients).
`
`Supraventricular Tachycardia
`
`In two multicenter, randomized, double-blind, controlled comparisons of BREVIBLOC
`(Esmolol Hydrochloride) with placebo and propranolol, maintenance doses of 50 to
`300 mcg/kg/min (0.05 to 0.3 mg/kg/min) of BREVIBLOC were found to be more
`effective than placebo and about as effective as propranolol, 3-6 mg given by bolus
`injections, in the treatment of supraventricular tachycardia, principally atrial fibrillation
`and atrial flutter. The majority of these patients developed their arrhythmias
`postoperatively. About 60-70% of the patients treated with BREVIBLOC had a desired
`therapeutic effect (either a 20% reduction in heart rate, a decrease in heart rate to less
`than 100 bpm, or, rarely, conversion to NSR) and about 95% of those who responded did
`so at a dosage of 200 mcg/kg/min (0.2 mg/kg/min) or less. The average effective dosage
`of BREVIBLOC was approximately 100-115 mcg/kg/min (0.1-0.115 mg/kg/min) in the
`two studies. Other multicenter baseline-controlled studies gave essentially similar results.
`In the comparison with propranolol, about 50% of patients in both the BREVIBLOC and
`propranolol groups were on concomitant digoxin. Response rates were slightly higher
`with both beta blockers in the digoxin-treated patients.
`
`In all studies significant decreases of blood pressure occurred in 20-50% of patients,
`identified either as adverse reaction reports by investigators, or by observation of systolic
`pressure less than 90 mmHg or diastolic pressure less than 50 mmHg. The hypotension
`was symptomatic (mainly diaphoresis or dizziness) in about 12% of patients, and therapy
`was discontinued in about 11% of patients, about half of whom were symptomatic. In
`comparison to propranolol, hypotension was about three times as frequent with
`BREVIBLOC, 53% vs. 17%. The hypotension was rapidly reversible with decreased
`infusion rate or after discontinuation of therapy with BREVIBLOC. For both
`BREVIBLOC and propranolol, hypotension was reported less frequently in patients
`receiving concomitant digoxin.
`
`INDICATIONS AND USAGE
`
`Supraventricular 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
`
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`tachycardia where, in the physician’s judgment, the rapid heart rate requires specific
`intervention. BREVIBLOC is not intended for use in chronic settings where transfer to
`another agent is anticipated.
`
`Intraoperative and Postoperative Tachycardia and/or Hypertension
`
`BREVIBLOC (Esmolol Hydrochloride) is indicated for the 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.
`
`CONTRAINDICATIONS
`
`BREVIBLOC (Esmolol Hydrochloride) is contraindicated in patients with sinus
`bradycardia, heart block greater than first degree, cardiogenic shock or overt heart failure
`(see WARNINGS).
`
`WARNINGS
`
`Hypotension
`
`In clinical trials 20-50% of patients treated with BREVIBLOC (Esmolol Hydrochloride)
`have experienced hypotension, generally defined as systolic pressure less than 90 mmHg
`and/or diastolic pressure less than 50 mmHg. About 12% of the patients have been
`symptomatic (mainly diaphoresis or dizziness). Hypotension can occur at any dose but is
`dose-related so that doses beyond 200 mcg/kg/min (0.2 mg/kg/min) are not
`recommended. Patients should be closely monitored, especially if pretreatment blood
`pressure is low. Decrease of dose or termination of infusion reverses hypotension, usually
`within 30 minutes.
`
`Cardiac Failure
`
`Sympathetic stimulation is necessary in supporting circulatory function in congestive
`heart failure, and beta blockade carries the potential hazard of further depressing
`myocardial contractility and precipitating more severe failure. Continued depression of
`the myocardium with beta blocking agents over a period of time can, in some cases, lead
`to cardiac failure. At the first sign or symptom of impending cardiac failure,
`BREVIBLOC (Esmolol Hydrochloride) should be withdrawn. Although withdrawal may
`be sufficient because of the short elimination half-life of BREVIBLOC, specific
`
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`treatment may also be considered (see OVERDOSAGE). The use of BREVIBLOC for
`control of ventricular response in patients with supraventricular arrhythmias should be
`undertaken with caution when the patient is compromised hemodynamically or is taking
`other drugs that decrease any or all of the following: peripheral resistance, myocardial
`filling, myocardial contractility, or electrical impulse propagation in the myocardium.
`Despite the rapid onset and offset of the effects of BREVIBLOC, several cases of death
`have been reported in complex clinical states where BREVIBLOC was presumably being
`used to control ventricular rate.
`
`Intraoperative and Postoperative Tachycardia and/or Hypertension
`
`BREVIBLOC (Esmolol Hydrochloride) should not be used as the treatment for
`hypertension in patients in whom the increased blood pressure is primarily due to the
`vasoconstriction associated with hypothermia.
`
`Bronchospastic Diseases
`
`PATIENTS WITH BRONCHOSPASTIC DISEASES SHOULD, IN GENERAL, NOT
`RECEIVE BETA BLOCKERS. Because of its relative beta1 selectivity and titratability,
`BREVIBLOC (Esmolol Hydrochloride) may be used with caution in patients with
`bronchospastic diseases. However, since beta1 selectivity is not absolute, BREVIBLOC
`should be carefully titrated to obtain the lowest possible effective dose. In the event of
`bronchospasm, the infusion should be terminated immediately; a beta2 stimulating agent
`may be administered if conditions warrant but should be used with particular caution as
`patients already have rapid ventricular rates.
`
`Diabetes Mellitus and Hypoglycemia
`
`BREVIBLOC (Esmolol Hydrochloride) should be used with caution in diabetic patients
`requiring a beta blocking agent. Beta blockers may mask tachycardia occurring with
`hypoglycemia, but other manifestations such as dizziness and sweating may not be
`significantly affected.
`
`PRECAUTIONS
`
`General
`
`Because the acid metabolite of BREVIBLOC is primarily excreted unchanged by the
`kidney, BREVIBLOC (Esmolol Hydrochloride) should be administered with caution to
`patients with impaired renal function. The elimination half-life of the acid metabolite was
`
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`

`prolonged ten-fold and the plasma level was considerably elevated in patients with
`end-stage renal disease.
`
`Drug Interactions
`
`Catecholamine-depleting drugs, e.g., reserpine, may have an additive effect when given
`with beta blocking agents. Patients treated concurrently with BREVIBLOC (Esmolol
`Hydrochloride) and a catecholamine depletor should therefore be closely observed for
`evidence of hypotension or marked bradycardia, which may result in vertigo, syncope, or
`postural hypotension.
`
`A study of interaction between BREVIBLOC and warfarin showed that concomitant
`administration of BREVIBLOC and warfarin does not alter warfarin plasma levels.
`BREVIBLOC concentrations were equivocally higher when given with warfarin, but this
`is not likely to be clinically important.
`
`When digoxin and BREVIBLOC were concomitantly administered intravenously to
`normal volunteers, there was a 10-20% increase in digoxin blood levels at some time
`points. Digoxin did not affect BREVIBLOC pharmacokinetics. When intravenous
`morphine and BREVIBLOC were concomitantly administered in normal subjects, no
`effect on morphine blood levels was seen, but BREVIBLOC steady-state blood levels
`were increased by 46% in the presence of morphine. No other pharmacokinetic
`parameters were changed.
`
`The effect of BREVIBLOC on the duration of succinylcholine-induced neuromuscular
`blockade was studied in patients undergoing surgery. The onset of neuromuscular
`blockade by succinylcholine was unaffected by BREVIBLOC, but the duration of
`neuromuscular blockade was prolonged from 5 minutes to 8 minutes.
`
`Although the interactions observed in these studies do not appear to be of major clinical
`importance, BREVIBLOC should be titrated with caution in patients being treated
`concurrently with digoxin, morphine, succinylcholine or warfarin.
`
`While taking beta blockers, patients with a history of severe anaphylactic reaction to a
`variety of allergens may be more reactive to repeated challenge, either accidental,
`diagnostic, or therapeutic. Such patients may be unresponsive to the usual doses of
`epinephrine used to treat allergic reaction.
`
`Caution should be exercised when considering the use of BREVIBLOC and verapamil in
`patients with depressed myocardial function. Fatal cardiac arrests have occurred in
`
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`

`patients receiving both drugs. Additionally, BREVIBLOC should not be used to control
`supraventricular tachycardia in the presence of agents which are vasoconstrictive and
`inotropic such as dopamine, epinephrine, and norepinephrine because of the danger of
`blocking cardiac contractility when systemic vascular resistance is high.
`
`Carcinogenesis, Mutagenesis, Impairment of Fertility
`
`Because of its short term usage no carcinogenicity, mutagenicity or reproductive
`performance studies have been conducted with BREVIBLOC (Esmolol Hydrochloride).
`
`Pregnancy Category C
`
`Teratogenicity studies in rats at intravenous dosages of BREVIBLOC (Esmolol
`Hydrochloride) up to 3000 mcg/kg/min (3 mg/kg/min) (ten 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 (10 mg/kg/min)
`produced maternal toxicity and lethality. In rabbits, intravenous dosages up to
`1000 mcg/kg/min (1 mg/kg/min) for 30 minutes daily produced no evidence of maternal
`toxicity, embryotoxicity or teratogenicity, while 2500 mcg/kg/min (2.5 mg/kg/min)
`produced minimal maternal toxicity and increased fetal resorptions.
`
`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.
`
`Nursing Mothers
`
`It is not known whether BREVIBLOC (Esmolol Hydrochloride) is excreted in human
`milk; however, caution should be exercised when BREVIBLOC is administered to a
`nursing woman.
`
`Pediatric Use
`
`The safety and effectiveness of BREVIBLOC (Esmolol Hydrochloride) in pediatric
`patients have not been established.
`
`ADVERSE REACTIONS
`
`The following adverse reaction rates are based on use of BREVIBLOC (Esmolol
`Hydrochloride) in clinical trials involving 369 patients with supraventricular tachycardia
`
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`

`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 adverse effect has been hypotension (see WARNINGS). 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, Cardiac Failure).
`
`Cardiovascular
`
`Symptomatic hypotension (diaphoresis, dizziness) occurred in 12% of patients, and
`therapy was discontinued in about 11%, about half of whom were symptomatic.
`Asymptomatic hypotension occurred in about 25% of patients. Hypotension resolved
`during BREVIBLOC (Esmolol Hydrochloride) infusion in 63% of these patients and
`within 30 minutes after discontinuation of infusion in 80% of the remaining patients.
`Diaphoresis accompanied hypotension in 10% of patients. Peripheral ischemia occurred
`in approximately 1% of patients. Pallor, flushing, bradycardia (heart rate less than 50
`beats per minute), chest pain, syncope, pulmonary edema and heart block have each been
`reported in less than 1% of patients. In two patients without supraventricular tachycardia
`but with serious coronary artery disease (post inferior myocardial infarction or unstable
`angina), severe bradycardia/sinus pause/asystole has developed, reversible in both cases
`with discontinuation of treatment.
`
`Central Nervous System
`
`Dizziness has occurred in 3% of patients; somnolence in 3%; confusion, headache, and
`agitation in about 2%; and fatigue in about 1% of patients. Paresthesia, asthenia,
`depression, abnormal thinking, anxiety, anorexia, and lightheadedness were reported in
`less than 1% of patients. Seizures were also reported in less than 1% of patients, with
`one death.
`
`Respiratory
`
`Bronchospasm, wheezing, dyspnea, nasal congestion, rhonchi, and rales have each been
`reported in less than 1% of patients.
`
`Gastrointestinal
`
`Nausea was reported in 7% of patients. Vomiting has occurred in about 1% of patients.
`Dyspepsia, constipation, dry mouth, and abdominal discomfort have each occurred in less
`than 1% of patients. Taste perversion has also been reported.
`
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`

`Skin (Infusion Site)
`
`Infusion site reactions including inflammation and induration were reported in about 8%
`of patients. Edema, erythema, skin discoloration, burning at the infusion site,
`thrombophlebitis, and local skin necrosis from extravasation have each occurred in less
`than 1% of patients.
`
`Miscellaneous
`
`Each of the following has been reported in less than 1% of patients: Urinary retention,
`speech disorder, abnormal vision, midscapular pain, rigors, and fever.
`
`OVERDOSAGE
`
`Acute Toxicity
`
`Overdoses of BREVIBLOC (Esmolol Hydrochloride) can cause cardiac arrest. In
`addition, overdoses can produce bradycardia, hypotension, electromechanical
`dissociation and loss of consciousness. Cases of massive accidental overdoses of
`BREVIBLOC have occurred due to 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 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.
`
`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, the following general measures should also
`be considered.
`
`Bradycardia: Intravenous administration of atropine or another anticholinergic drug.
`
`Bronchospasm: Intravenous administration of a beta2 stimulating agent and/or a
`theophylline derivative.
`
`Cardiac Failure: Intravenous administration of a diuretic and/or digitalis glycoside. In
`shock resulting from inadequate cardiac contractility, intravenous administration of
`dopamine, dobutamine, isoproterenol, or amrinone may be considered.
`
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`Symptomatic Hypotension: Intravenous administration of fluids and/or pressor agents.
`
`DOSAGE AND ADMINISTRATION
`
`Dosing Information:
`
`SUPRAVENTRICULAR TACHYCARDIA
`
`Dosage needs to be titrated, using ventricular rate as the guide.
`
`An initial loading dose of 0.5 milligrams/kg (500 micrograms/kg) infused over a minute
`duration followed by a maintenance infusion of 0.05 milligrams/kg/min
`(50 micrograms/kg/min) for the next 4 minutes is recommended. This should give a
`rough guide with respect to the responsiveness of ventricular rate.
`
`After the 4 minutes of initial maintenance infusion (total treatment duration being
`5 minutes), depending upon the desired ventricular response, the maintenance infusion
`may be continued at 0.05 mg/kg/min or increased step-wise (e.g. 0.1 mg/kg/min,
`0.15 mg/kg/min to a maximum of 0.2 mg/kg/min) with each step being maintained for
`4 or more minutes.
`
`If more rapid slowing of ventricular response is imperative, the 0.5 mg/kg loading dose
`infused over a 1 minute period may be repeated, followed by a maintenance infusion of
`0.1 mg/kg/min for 4 minutes. Then, depending upon ventricular rate, another (and final)
`loading dose of 0.5 mg/kg/min infused over a 1 minute period may be administered
`followed by a maintenance infusion of 0.15 mg/kg/min. If needed, after 4 minutes of the
`0.15 mg/kg/min maintenance infusion, the maintenance infusion may be increased to a
`maximum of 0.2 mg/kg/min.
`
`In the absence of loading doses, constant infusion of a single concentration of esmolol
`reaches pharmacokinetic and pharmacodynamic steady-state in about 30 minutes.
`Maintenance infusions (with or without loading doses) may be continued for as long as
`24 hours.
`
`The following table summarizes the above and assumes that 3 loading doses (the
`maximum recommended) are infused over 1 minute and incremental maintenance doses
`are required after each loading dose. There should be no 4th loading dose, but the
`maintenance dose may be incremented one more time.
`
`14
`
`

`

`Elapsed
`Time
`
`(minutes)
`0 – 1
`1 – 5
`5 – 6
`6 – 10
`10 – 11
`11 – 15
`15 – 16
`16 - 20
`> 20
`
`Loading Dose
`(over 1 minute)
`micrograms/kg/min
`milligrams/kg/min
`500
`0.5
`
`
`500
`0.5
`
`
`500
`0.5
`
`
`•
`•
`
`
`
`
`
`Maintenance Dose
`(over 4 minutes)
`micrograms/kg/min
`milligrams/kg/min
`
`
`50
` 0.05
`
`
`100
`0.1
`
`
`150
` 0.15
`
`
`*200
`*0.2
`Maintenance dose titrated to heart rate or other
`clinical endpoint.
`*As the desired heart rate or endpoint is approached, the loading infusion may be omitted and the maintenance
`infusion titrated to 300 mcg/kg/min (0.3 mg/kg/min) or downward as appropriate. Maintenance dosages above
`200 mcg/kg/min (0.2 mg/kg/min) have not been shown to have significantly increased benefits. The interval
`between titration steps may be increased.
`
`In the treatment of supraventricular tachycardia, responses to BREVIBLOC
`(Esmolol Hydrochloride) usually (over 95%) occur within the range of 50 to
`200 micrograms/kg/min (0.05 to 0.2 milligrams/kg/min). The average effective dosage is
`approximately 100 micrograms/kg/min (0.1 milligrams/kg/min) although dosages as low
`as 25 micrograms/kg/min (0.025 milligrams/kg/min) have been adequate in some
`patients. Dosages as high as 300 micrograms/kg/min (0.3 milligrams/kg/min) have been
`used, but these provide little added effect and increase the rate of adverse effects, so
`doses greater than 200 micrograms/kg/min are not recommended. Dosage of
`BREVIBLOC in supraventricular tachycardia must be individualized by titration in
`which each step consists of a loading dosage followed by a maintenance dosage.
`
`This specific dosage regimen has not been studied intraoperatively and, because of the
`time required for titration, may not be optimal for intraoperative use.
`
`The safety of dosages above 300 mcg/kg/min (0.3 mg/kg/min) has not been studied.
`
`In the event of an adverse reaction, the dosage of BREVIBLOC may be reduced or
`discontinued. If a local infusion site reaction develops, an alternate infusion site should
`be used and caution should be taken to prevent extravasation. The use of butterfly needles
`should be avoided.
`
`15
`
`

`

`Abrupt cessation of BREVIBLOC in patients has not been reported to produce the
`withdrawal effects which may occur with abrupt withdrawal of beta blockers following
`chronic use in coronary artery disease (CAD) patients. However, caution should still be
`used in abruptly discontinuing infusions of BREVIBLOC in CAD patients.
`
`After achieving an adequate control of the heart rate and a stable clinical status in patients
`with supraventricular tachycardia, transition to alternative antiarrhythmic agents such as
`propranolol, digoxin, or verapamil, may be accomplished.
`
`A recommended guideline for such a transition is given below but the physician should
`carefully consider the labeling instructions for the alternative agent selected.
`
`Alternative Agent
`
`Dosage
`
`Propranolol hydrochloride
`
`10-20 mg q 4-6 hrs
`
`Digoxin
`
`Verapamil
`
`0.125-0.5 mg q 6 hrs (p.o. or i.v.)
`
`80 mg q 6 hrs
`
`
`The dosage of BREVIBLOC (Esmolol Hydrochloride) should be reduced as follows:
`
`1. Thirty minutes following the first dose of the alternative agent, reduce the
`infusion rate of BREVIBLOC by one-half (50%).
`2. Following the second dose of the alternative agent, monitor the patient’s response
`and if satisfactory control is maintained for the first hour, discontinue
`BREVIBLOC.
`The use of infusions of BREVIBLOC up to 24 hours has been well documented; in
`addition, limited data from 24-48 hrs (N=48) indicate that BREVIBLOC is well tolerated
`up to 48 hours.
`
`INTRAOPERATIVE AND POSTOPERATIVE TACHYCARDIA AND/OR
`HYPERTENSION
`
`In the intraoperative and postoperative settings it is not always advisable to slowly titrate
`the dose of BREVIBLOC (Esmolol Hydrochloride) to a therapeutic effect. Therefore,
`t