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Dobutamine
Dobutamine Injection, USP is the hydrochloride salt of 1,2-benzenediol,4-[2-[3-(4-hydroxyphenyl)-1-methylpropyl] amino]ethyl]-,(±)- It is a synthetic catecholamine. Its molecular formula is C18H23NO3 and its molecular weight is 301.39. The clinical formulation
is supplied in a sterile
form for intravenous use
only. Each mL contains 12.5 mg
(41.5 pmol) dobutamine, 0.24 mg
sodium bisulfite (added during manufacture), and water
for injection, q.s. Hydrochloric acid and/or sodium
hydroxide may have
been added during manufacture to adjust the pH.
Dobutamine is a direct-acting inotropic agent whose primary activity results from stimulation of the b-receptors of the heart while producing comparatively mild chronotropic, hypertensive, arrhythmogenic, and vasodilative effects. It does not cause the release of endogenous norepinephrine, as does dopamine. In animal studies, dobutamine produces less increase in heart rate and less decrease in peripheral vascular resistance for a given inotropic effect than does isoproterenol. In patients with depressed cardiac function, both dobutamine and isoproterenol increase the cardiac output to a similar degree. In the case of dobutamine, this increase is usually not accompanied by marked increases in heart rate (although tachycardia is occasionally observed), and the cardiac stroke volume is usually increased. In contrast, isoproterenol increases the cardiac index primarily by increasing the heart rate while stroke volume changes little or declines. Facilitation of atrioventricular conduction has been observed in human electrophysiologic studies and in patients with atrial fibrillation. Systemic vascular resistance is usually decreased with administration of dobutamine. Occasionally, minimum vasoconstriction has been observed. Most clinical experience
with dobutamine is short-term — not more than several hours in duration.
In the limited number
of patients who were studied for 24, 48, and 72 hours, a persistent
increase in cardiac
output occurred in some,
whereas output returned
toward baseline values
in others. The onset of action
of dobutamine is within 1 to 2 minutes; however, as much as 10 minutes
may be required to obtain the peak effect
of a particular infusion rate. The plasma
half-life of dobutamine
in humans is 2 minutes. The principal
routes of metabolism
are methylation
of the catechol and conjugation. In
human urine, the major
excretion products
are the conjugates of dobutamine and 3-0-methyl dobutamine. The
3-0-methyl derivative
of dobutamine is inactive. Alteration of synaptic
concentrations of catecholamines with either reserpine
or tricyclic antidepressants does not alter the actions of dobutamine
in animals, which indicates that the actions of dobutamine are not
dependent on presynaptic
mechanisms. The effective infusion
rate of dobutamine varies widely from patient
to patient, and titration
is always necessary (see DOSAGE
AND ADMINISTRATION). At least in pediatric
patients, dobutamine- induced
increases in cardiac output and systemic
pressure are generally
seen, in any given patient, at lower infusion
rates than those that cause
substantial tachycardia
(see PRECAUTIONS: Pediatric
Use).
Dobutamine is indicated when parenteral therapy is necessary for inotropic support in the short- term treatment of patients with cardiac decompensation due to depressed contractility resulting either from organic heart disease or from cardiac surgical procedures. Experience with intravenous dobutamine in controlled trials does not extend beyond 48 hours of repeated boluses and/ or continuous infusions. Whether given orally, continuously intravenously, or intermittently intravenously, neither dobutamine nor any other cyclic-AMP-dependent inotrope has been shown in controlled trials to be safe or effective in the long- term treatment of congestive heart failure. In controlled trials of chronic oral therapy with various such agents, symptoms were not consistently alleviated, and the cyclic-AMP-dependent inotropes were consistently associated with increased risk of hospitalization and death. Patients with NYHA Class IV symptoms appeared to be at particular risk.
Note: Do not add dobutamine to 5% Sodium Bicarbonate Injection or to any other strongly alkaline solution. Because of potential physical incompatibilities, it is recommended that dobutamine not be mixed with other drugs in the same solution. Dobutamine should not be used in conjunction with other agents or diluents containing both sodium bisulfite and ethanol. Preparation and Stability At the time of administration, dobutamine must be further diluted in an IV container to at least a 50-mL solution using one of the following intravenous solutions as a diluent: 5% Dextrose Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 10% Dextrose Injection, lsolyte® M with 5% Dextrose Injection, Lactated Ringer’s Injection, 5% Dextrose in Lactated Ringer’s Injection, Normosol® M in D5-W, 20% Osmitrol® in Water for Injection, 0.9% Sodium Chloride Injection, or Sodium Lactate Injection. Intravenous solutions should be used within 24 hours. Recommended Dosage Infusion of dobutamine should be started at a low rate (0.5-1.0 µg/kg/min) and titrated at intervals of a few minutes, guided by the patient’s response, including systemic blood pressure, urine flow, frequency of ectopic activity, heart rate, and (whenever possible) measurements of cardiac output, central venous pressure, and/or pulmonary capillary wedge pressure. In reported trials, the optimal infusion rates have varied from patient to patient, usually 2-20 µg/kg/min but sometimes slightly outside of this range. On rare occasions, infusion rates up to 40 µg/kg/min have been required to obtain the desired effect. Rates of infusion (mL/h) for dobutamine concentrations of 500 µg/mL, 1,000 µg/mL, and 2,000 µg/mL necessary to attain various delivery rates of dobutamine (µg/kg/min) for patients of different weights are given in Table 1. TABLE 1
Concentrations of up to 5,000 pg/mL have been administered to humans (250 mg/50 mL). The final volume administered should be determined by the fluid requirements of the patient. Intravenous drug products should be inspected visually and should not be used if particulate matter or discoloration is present. HOW SUPPLIED Vials: Each 20 mL vial contains 250 mg dobutamine. NDC 0002-7375-01 (UC5339) — 1 s NDC 0002-7375-10 (UC5339) — Traypakt of 10 Store at controlled room
temperature, 59° to 86° F (15° to 30° C).
Increased Heart Rate, Blood Pressure, and Ventricular Ectopic Activity A 10- to 20- mm increase in systolic blood pressure and an increase in heart rate of 5 to 15 beats/minute have been noted in most patients (see WARNINGS regarding exaggerated chronotropic and pressor effects). Approximately 5% of adult patients have had increased premature ventricular beats during infusions. These effects are dose related. Hypotension Precipitous decreases in blood pressure have occasionally been described in association with dobutamine therapy. Decreasing the dose or discontinuing the infusion typically results in rapid return of blood pressure to baseline values. In rare cases, however, intervention may be required and reversibility may not be immediate. Reactions at Sites of Intravenous Infusion Phlebitis has occasionally been reported. Local inflammatory changes have been described following inadvertent infiltration. Isolated cases of cutaneous necrosis (destruction of skin tissue) have been reported. Miscellaneous Uncommon Effects The following adverse effects have been reported in 1% to 3% of adult patients: nausea, headache, anginal pain, nonspecific chest pain, palpitations, and shortness of breath. Isolated cases of thrombocytopenia have been reported. Administration of dobutamine, like other catecholamines, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels (see PRECAUTIONS).
Animal studies indicate that dobutamine may be ineffective if the patient has recently received a b-blocking drug. In such a case, the peripheral vascular resistance may increase. Preliminary studies indicate that the concomitant use of dobutamine and nitroprusside results in a higher cardiac output and, usually, a lower pulmonary wedge pressure than when either drug is used alone. There was no evidence
of drug interactions in
clinical studies in
which dobutamine was administered concurrently with other drugs,
including digitalis preparations, furosemide, spironolactone, lidocaine,
glyceryl trinitrate,
isosorbide dinitrate, morphine, atropine, heparin, protamine, potassium
chloride, folic acid, and acetaminophen.
Increase in Heart Rate or Blood Pressure Dobutamine may cause a marked increase in heart rate or blood pressure, especially systolic pressure. Approximately 10% of adult patients in clinical studies have had rate increases of 30 beats/minute or more, and about 7.5% have had a 50 mm Hg or greater increase in systolic pressure. Usually, reduction of dosage promptly reverses these effects. Because dobutamine facilitates atrioventricular conduction, patients with atrial fibrillation are at risk of developing rapid ventricular response. In patients who have atrial fibrillation with rapid ventricular response, a digitalis preparation should be used prior to institution of therapy with dobutamine. Patients with preexisting hypertension appear to face an increased risk of developing an exaggerated pressor response. Ectopic Activity Dobutamine may precipitate or exacerbate ventricular ectopic activity, but it rarely has caused ventricular tachycardia. Hypersensitivity Reactions suggestive of hypersensitivity associated with administration of dobutamine, including skin rash, fever, eosinophilia, and bronchospasm, have been reported occasionally. Dobutamine contains sodium bisulfite, a sulfite that may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes, in certain susceptible people. The overall prevalence of sulfite sensitivity in the general population is unknown and probably low. Sulfite sensitivity is seen more frequently in asthmatic than in nonasthmatic people.
General During the administration of dobutamine, as with any adrenergic agent, ECG and blood pressure should be continuously monitored. In addition, pulmonary wedge pressure and cardiac output should be monitored whenever possible to aid in the safe and effective infusion of dobutamine. Hypovolemia should be corrected with suitable volume expanders before treatment with dobutamine is instituted. No improvement may be observed in the presence of marked mechanical obstruction, such as severe valvular aortic stenosis. Usage Following Acute Myocardial Infarction Clinical experience with dobutamine following myocardial infarction has been insufficient to establish the safety of the drug for this use. There is concern that any agent that increases contractile force and heart rate may increase the size of an infarction by intensifying ischemia, but it is not known whether dobutamine does so. Laboratory Tests Dobutamine, like other b2- agonists, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels. Accordingly, consideration should be given to monitoring serum potassium. Drug Interactions Animal studies indicate that dobutamine may be ineffective if the patient has recently received a b-blocking drug. In such a case, the peripheral vascular resistance may increase. Preliminary studies indicate that the concomitant use of dobutamine and nitroprusside results in a higher cardiac output and, usually, a lower pulmonary wedge pressure than when either drug is used alone. There was no evidence of drug interactions in clinical studies in which dobutamine was administered concurrently with other drugs, including digitalis preparations, furosemide, spironolactone, lidocaine, glyceryl trinitrate, isosorbide dinitrate, morphine, atropine, heparin, protamine, potassium chloride, folic acid, and acetaminophen. Carcinogenesis, Mutagenesis, Impairment of Fertility Studies to evaluate the carcinogenic or mutagenic potential of dobutamine, or its potential to affect fertility, have not been conducted. Pregnancy Teratogenic Effects: Pregnancy Category B: Reproduction studies performed in rats at doses up to the normal human dose (10 µg/kg/min for 24 h, total daily dose of 14.4 mg/kg), and in rabbits at doses up to twice the normal human dose, have revealed no evidence of harm to the fetus due to dobutamine. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed. Labor and Delivery The effect of dobutamine on labor and delivery is unknown. Nursing Mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when dobutamine is administered to a nursing woman. If a mother requires dobutamine treatment, breast- feeding should be discontinued for the duration of the treatment. Pediatric Use Dobutamine has been shown to increase cardiac
output and systemic
pressure in pediatric
patients of every age group.
In premature
neonates, however, dobutamine is less effective than dopamine in
raising systemic blood
pressure without causing undue tachycardia, and dobutamine has not
been shown to provide any added benefit
when given to such infants already receiving optimal infusions of
dopamine.
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