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 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).
BREVIBLOC CONCENTRATE
BREVIBLOC CONCENTRATE is a clear, colorless to light yellow, sterile, nonpyrogenic concentrate.
2500 mg, 10 mL Ampul —Each mL contains 250 mg Esmolol Hydrochloride in 25% Propylene Glycol, USP, 25% Alcohol, USP and Water for Injection, USP; buffered with 17.0 mg Sodium Acetate Trihydrate, USP, and 0.00715 mL Glacial Acetic Acid, USP. Sodium Hydroxide and/or Hydrochloric Acid added, as necessary, to adjust pH to 3.5-5.5. NOT FOR DIRECT INTRAVENOUS USE - AMPUL MUST BE DILUTED PRIOR TO INFUSION. See DOSAGE AND ADMINISTRATION, Directions for Use of the Brevibloc Concentrate 10 mL Ampul (250 milligrams/mL).
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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 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.
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 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.
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