ESMOLOL HCL
DESCRIPTION:
MINIBLOCK (esmolol HCl) is a beta1-selective (cardioselective) adrenergic
receptor blocking agent with a very short duration of action (elimination half-
life is approximately 9 minutes). Esmolol HCl is:
()-Methyl p-(2-hydroxy-3-(isopropylamino) propoxy) hydrocinnamate
hydrochloride.
Esmolol HCl has the empirical formula C16H26NO4Cl and a molecular weight of
331.8. It has one asymmetric center and exists as an enantiomeric pair.
Esmolol HCl 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.
ACTIONS/CLINICAL PHARMACOLOGY:
MINIBLOCK (esmolol HCl) 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. MINIBLOCK 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
MINIBLOCK (esmolol HCl) 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 MINIBLOCK is not limited by the rate of blood
flow to metabolizing tissues such as the liver or affected by hepatic or renal
blood flow. MINIBLOCK 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 MINIBLOCK 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 MINIBLOCK 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
MINIBLOCK 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 MINIBLOCK, 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 MINIBLOCK.
Metabolism of MINIBLOCK 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 MINIBLOCK 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.
MINIBLOCK 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 MINIBLOCK (esmolol HCl), showing reduction in heart rate
at rest and during exercise, and attenuation of isoproterenol- induced increases
in heart rate. Blood levels of MINIBLOCK 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, MINIBLOCK 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, MINIBLOCK, 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, MINIBLOCK 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 MINIBLOCK 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 MINIBLOCK infusion, all of the hemodynamic parameters had
returned to pretreatment levels.
The relative cardioselectivity of MINIBLOCK was demonstrated in 10 mildly
asthmatic patients. Infusions of MINIBLOCK (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), MINIBLOCK
produced slightly enhanced bronchomotor sensitivity to dry air stimulus. These
effects were not clinically significant, and MINIBLOCK 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 MINIBLOCK
for treatment of supraventricular tachycardia (51 patients) or in perioperative
settings (32 patients).
SUPRAVENTRICULAR TACHYCARDIA
In two multicenter, randomized, double-blind, controlled comparisons of
MINIBLOCK (esmolol HCl) with placebo and propranolol, maintenance doses of 50
to 300 mcg/kg/min (0.05 to 0.3 mg/kg/min) of MINIBLOCK 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
MINIBLOCK 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 MINIBLOCK 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 MINIBLOCK 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 MINIBLOCK, 53% vs. 17%. The
hypotension was rapidly reversible with decreased infusion rate or after
discontinuation of therapy with MINIBLOCK. For both MINIBLOCK and
propranolol, hypotension was reported less frequently in patients receiving
concomitant digoxin.
INDICATIONS AND USAGE:
SUPRAVENTRICULAR TACHYCARDIA
MINIBLOCK (esmolol HCl) 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. MINIBLOCK is also
indicated in noncompensatory sinus tachycardia where, in the physician's
judgment, the rapid heart rate requires specific intervention. MINIBLOCK is
not intended for use in chronic settings where transfer to another agent is
anticipated.
INTRAOPERATIVE AND POSTOPERATIVE TACHYCARDIA AND/OR HYPERTENSION
MINIBLOCK (esmolol HCl) 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 MINIBLOCK to prevent such events is not recommended.
CONTRAINDICATIONS:
MINIBLOCK (esmolol HCl) 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 MINIBLOCK (esmolol HCl)
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, MINIBLOCK (esmolol HCl) should be
withdrawn. Although withdrawal may be sufficient because of the short
elimination half-life of MINIBLOCK, specific treatment may also be considered
(see OVERDOSAGE). The use of MINIBLOCK 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 MINIBLOCK, several cases
of death have been reported in complex clinical states where MINIBLOCK was
presumably being used to control ventricular rate.
INTRAOPERATIVE AND POSTOPERATIVE TACHYCARDIA AND/OR HYPERTENSION:
MINIBLOCK (esmolol HCl) 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,
MINIBLOCK (esmolol HCl) may be used with caution in patients with
bronchospastic diseases. However, since beta1 selectivity is not absolute,
MINIBLOCK 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:
MINIBLOCK (esmolol HCl) 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
Infusion concentrations of 20 mg/mL were associated with more serious venous
irritation, including thrombophlebitis, than concentrations of 10 mg/mL.
Extravasation of 20 mg/mL may lead to a serious local reaction and possible skin
necrosis. Concentrations greater than 10 mg/mL or infusion into small veins or
through a butterfly catheter should be avoided.
Because the acid metabolite of MINIBLOCK is primarily excreted unchanged by
the kidney, MINIBLOCK (esmolol HCl) should be administered with caution to
patients with impaired renal function. The elimination half-life of the acid
metabolite was prolonged ten-fold and the plasma level was considerably elevated
in patients with end-stage renal disease.
Care should be taken in the intravenous administration of MINIBLOCK as
sloughing of the skin and necrosis have been reported in association with
infiltration and extravasation of intravenous infusions.
DRUG INTERACTIONS
Catecholamine-depleting drugs, e.g., reserpine, may have an additive effect when
given with beta blocking agents. Patients treated concurrently with MINIBLOCK
(esmolol HCl) 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 MINIBLOCK and warfarin showed that concomitant
administration of MINIBLOCK and warfarin does not alter warfarin plasma
levels. MINIBLOCK concentrations were equivocally higher when given with
warfarin, but this is not likely to be clinically important.
When digoxin and MINIBLOCK 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 MINIBLOCK pharmacokinetics. When
intravenous morphine and MINIBLOCK were concomitantly administered in normal
subjects, no effect on morphine blood levels was seen, but MINIBLOCK steady-
state blood levels were increased by 46% in the presence of morphine. No other
pharmacokinetic parameters were changed.
The effect of MINIBLOCK on the duration of succinylcholine-induced
neuromuscular blockade was studied in patients undergoing surgery. The onset of
neuromuscular blockade by succinylcholine was unaffected by MINIBLOCK, 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, MINIBLOCK 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 MINIBLOCK and
verapamil in patients with depressed myocardial function. Fatal cardiac arrests
have occurred in patients receiving both drugs. Additionally, MINIBLOCK
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 MINIBLOCK (esmolol HCl).
PREGNANCY CATEGORY C
Teratogenicity studies in rats at intravenous dosages of MINIBLOCK (esmolol
HCl) 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. MINIBLOCK should be used during pregnancy only if the
potential benefit justifies the potential risk to the fetus.
NURSING MOTHERS
It is not known whether MINIBLOCK (esmolol HCl) is excreted in human milk;
however, caution should be exercised when MINIBLOCK is administered to a
nursing woman.
PEDIATRIC USE
The safety and effectiveness of MINIBLOCK (esmolol HCl) in children have not
been established.
DRUG INTERACTIONS:
Catecholamine-depleting drugs, e.g., reserpine, may have an additive effect when
given with beta blocking agents. Patients treated concurrently with MINIBLOCK
(esmolol HCl) 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 MINIBLOCK and warfarin showed that concomitant
administration of MINIBLOCK and warfarin does not alter warfarin plasma
levels. MINIBLOCK concentrations were equivocally higher when given with
warfarin, but this is not likely to be clinically important.
When digoxin and MINIBLOCK 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 MINIBLOCK pharmacokinetics. When
intravenous morphine and MINIBLOCK were concomitantly administered in normal
subjects, no effect on morphine blood levels was seen, but MINIBLOCK steady-
state blood levels were increased by 46% in the presence of morphine. No other
pharmacokinetic parameters were changed.
The effect of MINIBLOCK on the duration of succinylcholine-induced
neuromuscular blockade was studied in patients undergoing surgery. The onset of
neuromuscular blockade by succinylcholine was unaffected by MINIBLOCK, 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, MINIBLOCK 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 MINIBLOCK and
verapamil in patients with depressed myocardial function. Fatal cardiac arrests
have occurred in patients receiving both drugs. Additionally, MINIBLOCK
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.
(See Also PRECAUTIONS.)
ADVERSE REACTIONS:
The following adverse reaction rates are based on use of MINIBLOCK (esmolol
HCl) 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 adverse effect has been hypotension
(see WARNINGS). Deaths have been reported in post- marketing experience
occurring during complex clinical states where MINIBLOCK 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 MINIBLOCK (esmolol HCl) 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.
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 MINIBLOCK (esmolol HCl) can cause cardiac arrest. In addition,
overdoses can produce bradycardia, hypotension, electromechanical dissociation
and loss of consciousness. Cases of massive accidental overdoses of MINIBLOCK
have occurred due to 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 MINIBLOCK
resolved.
Because of its approximately 9-minute elimination half-life, the first step in
the management of toxicity should be to discontinue the MINIBLOCK 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 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.
SYMPTOMATIC HYPOTENSION: Intravenous administration of fluids and/or pressor
agents.
DOSAGE AND ADMINISTRATION:
2500 MG AMPUL
THE 2500 MG AMPUL IS NOT FOR DIRECT INTRAVENOUS INJECTION. THIS DOSAGE FORM IS A
CONCENTRATED, POTENT DRUG WHICH MUST BE DILUTED PRIOR TO ITS INFUSION.
MINIBLOCK SHOULD NOT BE ADMIXED WITH SODIUM BICARBONATE. MINIBLOCK SHOULD
NOT BE MIXED WITH OTHER DRUGS PRIOR TO DILUTION IN A SUITABLE INTRAVENOUS FLUID.
(See Compatability Section below.)
DILUTION: Aseptically prepare a 10 mg/mL infusion by adding two 2500 mg ampuls
to a 500 mL container or one 2500 mg ampul to a 250 mL container of a compatible
intravenous solution listed below. (Remove overage prior to dilution as
appropriate.) This yields a final concentration of 10 mg/mL. The diluted
solution is stable for at least 24 hours at room temperature. Note:
Concentrations of MINIBLOCK (esmolol HCl) greater than 10 mg/mL are likely to
produce irritation on continued infusion (see PRECAUTIONS). MINIBLOCK has,
however, been well tolerated when administered via a central vein.
100 MG VIAL
This dosage form is prediluted to provide a ready-to-use 10 mg/mL concentration
recommended for MINIBLOCK intravenous administration. It may be used to
administer the appropriate MINIBLOCK (esmolol HCl) loading dosage infusions
by hand-held syringe while the maintenance infusion is being prepared.
When using the 100 mg vial, a loading dose of 0.5mg/kg/min for a 70 kg patient
would be 3.5 mL.
SUPRAVENTRICULAR TACHYCARDIA
In the treatment of supraventricular tachycardia, responses to MINIBLOCK
(esmolol HCl) usually (over 95%) occur within the range of 50 to 200 mcg/kg/min
(0.05 to 0.2 mg/kg/min). The average effective dosage is approximately 100
mcg/kg/min (0.1 mg/kg/min) although dosages as low as 25 mcg/kg/min (0.025
mg/kg/min) have been adequate in some patients. Dosages as high as 300
mcg/kg/min (0.3 mg/kg/min) have been used, but these provide little added effect
and an increased rate of adverse effects, and are not recommended. Dosage of
MINIBLOCK in supraventricular tachycardia must be individualized by titration
in which each step consists of a loading dosage followed by a maintenance
dosage.
To initiate treatment of a patient with supraventricular tachycardia, administer
a loading infusion of 500 mcg/kg/min (0.5 mg/kg/min) over one minute followed by
a four-minute maintenance infusion of 50 mcg/kg/min (0.05 mg/kg/min). If an
adequate therapeutic effect is observed over the five minutes of drug
administration, maintain the maintenance infusion dosage with periodic
adjustments up or down as needed. If an adequate therapeutic effect is not
observed, the same loading dosage is repeated over one minute followed by an
increased maintenance infusion rate of 100 mcg/kg/min (0.1 mg/kg/min).
Continue titration procedure as above, repeating the original loading infusion
of 500 mcg/kg/min (0.5 mg/kg/min) over 1 minute, but increasing the maintenance
infusion rate over the subsequent four minutes by 50 mcg/kg/min (0.05 mg/kg/min)
increments. As the desired heart rate or blood pressure is approached, omit
subsequent loading doses and titrate the maintenance dosage up or down to
endpoint. Also, if desired, increase the interval between steps from 5 to 10
minutes.
LOADING DOSE MAINTENANCE DOSE
(over 1 minute) (over 4 minutes)
TIME mcg/kg/ mg/kg/ mcg/kg/ mg/kg/
(minutes) min min min min
----------- ----------- ----------- ----------- -------------
0-1 500 0.5
1-5 50 0.05
5-6 500 0.5
6-10 100 0.1
10-11 500 0.5
11-15 150 0.15
15-16 * *
16-20 (*)200 (*)0.2
20-(24 hrs) 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.
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 MINIBLOCK 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.
Abrupt cessation of MINIBLOCK 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 MINIBLOCK
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 0.125-0.5 mg q 6 hrs (p.o. or i.v.)
Verapamil 80 mg q 6 hrs
The dosage of MINIBLOCK (esmolol HCl) should be reduced as follows:
1. Thirty minutes following the first dose of the alternative agent, reduce the
infusion rate of MINIBLOCK 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 MINIBLOCK.
The use of infusions of MINIBLOCK up to 24 hours has been well documented; in
addition, limited data from 24-48 hrs (N=48) indicate that MINIBLOCK 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 MINIBLOCK (esmolol HCl) to a therapeutic effect.
Therefore, two dosing options are presented: immediate control dosing and a
gradual control when the physician has time to titrate.
1. IMMEDIATE CONTROL
For intraoperative treatment of tachycardia and/or hypertension give an 80 mg
(approximately 1 mg/kg) bolus dose over 30 seconds followed by a 150 mcg/kg/min
infusion, if necessary. Adjust the infusion rate as required up to 300
mcg/kg/min to maintain desired heart rate and/or blood pressure.
2. GRADUAL CONTROL
For postoperative tachycardia and hypertension, the dosing schedule is the same
as that used in supraventricular tachycardia. To initiate treatment, administer
a loading dosage infusion of 500 mcg/kg/min of MINIBLOCK for one minute
followed by a four-minute maintenance infusion of 50 mcg/kg/min. If an adequate
therapeutic effect is not observed within five minutes, repeat the same loading
dosage and follow with a maintenance infusion increased to 100 mcg/kg/min (see
above Supraventricular Tachycardia).
NOTE: Higher dosages (250-300 mcg/kg/min) may be required for adequate control
of blood pressure than those required for the treatment of atrial fibrillation,
flutter and sinus tachycardia. One third of the postoperative hypertensive
patients required these higher doses.
COMPATIBILITY WITH COMMONLY USE INTRAVENOUS FLUIDS
MINIBLOCK INJECTION was tested for compatibility with ten commonly used
intravenous fluids at a final concentration of 10 mg esmolol HCl per mL.
MINIBLOCK INJECTION 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
MINIBLOCK INJECTION was NOT compatible with Sodium Bicarbonate (5%)
Injection, USP.
NOTE: Parenteral drug products should be inspected visually for particulate
matter and discoloration prior to administration, whenever solution and
container permit.
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