DOBUTAMINE: 1,632 Adverse Event Reports & Safety Profile

DESCRIPTION Dobutamine Hydrochloride in 5% Dextrose Injection is a sterile, nonpyrogenic solution of Dobutamine Hydrochloride, USP and Dextrose, USP in Water for Injection, USP. Dobutamine hydrochloride is chemically designated as (±)-4-[2-[[3-(p-hydroxyphenyl)-1-methylpropyl]amino]ethyl]-pyrocatechol hydrochloride. It is a synthetic catecholamine.

Dextrose

Hydrous, USP is chemically designated as D-Glucopyranose monohydrate. Structural formulas are shown below: Dobutamine Hydrochloride, USP (D-Glucopyranose monohydrate)

Dextrose

Hydrous, USP Dobutamine Hydrochloride in 5% Dextrose Injection is intended for intravenous use only. It contains no antimicrobial agents. The pH is adjusted with sodium hydroxide and/or hydrochloric acid. Sodium bisulfite is added as a stabilizer. The solution is intended for single use only. When smaller doses are required, the unused portion should be discarded. Composition, osmolarity, pH and caloric content are given in Table 1.

Table

1.

Composition Approximately

5 mEq/L sodium bisulfite is added as a stabilizer.

Dobutamine

Hydrochloride in 5% Dextrose Injection. Dobutamine (mg/Container) Dobutamine (mcg/mL)

Dextrose

Hydrous, USP (g/L) Osmolarity (mOsmol/L) (calc) Normal physiologic osmolarity range is approximately 280 to 310 mOsmol/L. Administration of substantially hypertonic solutions (≥ 600 mOsmol/L) may cause vein damage. pH kcal/L 250 mg/250 mL 1000 50 259 3.5 (2.5 to 5.5) 170 500 mg/250 mL 2000 50 266 3.5 (2.5 to 5.5) 170 1000 mg/250 mL 4000 50 280 3.5 (2.5 to 5.5) 170 This Viaflex Plus plastic container is fabricated from a specially formulated polyvinyl chloride (PL 2207 Plastic). Viaflex containers, including Viaflex Plus containers, are made of flexible plastic and are for parenteral use.

Viaflex

Plus on the container indicates the presence of a drug additive in a drug vehicle. The amount of water that can permeate from inside the container into the overwrap is insufficient to affect the solution significantly. Solutions in contact with the plastic container can leach out certain of its chemical components in very small amounts within the expiration period, e.g., di-2-ethylhexyl phthalate (DEHP), up to 5 parts per million; however, the safety of the plastic has been confirmed in tests in animals according to USP biological tests for plastic containers as well as by tissue culture toxicity studies.

Dobutamine Hydrochloride Structural

Formula D-Glucopyranose monohydrate - Dextrose Hydrous Structural Formula

INDICATIONS AND USAGE Dobutamine Hydrochloride in 5% Dextrose Injection 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 risks of hospitalization and death. Patients with NYHA Class IV symptoms appeared to be at particular risk.

DOSAGE AND ADMINISTRATION 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, Isolyte ® 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 to 1 mcg/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 to 20 mcg/kg/min but sometimes slightly outside of this range. On rare occasions, infusion rates up to 40 mcg/kg/min have been required to obtain the desired effect. Rates of infusion (mL/h) for dobutamine concentrations of 500 mcg/mL, 1000 mcg/mL, and 2000 mcg/mL necessary to attain various delivery rates of dobutamine (mcg/kg/min) for patients of different weights are given in Table 1.

Table

1 Dobutamine Injection USP Infusion Rate (mL/h) for 500 mcg/mL concentration Drug Delivery Rate Patient Body Weight (kg) (mcg/kg/min) 5 10 20 30 40 50 60 70 80 90 100 110 0.5 0.3 0.6 1.2 1.8 2.4 3 3.6 4.2 4.8 5.4 6 6.6 1 0.6 1.2 2.4 3.6 4.8 6 7.2 8.4 9.6 10.8 12 13.2 2.5 1.5 3 6 9 12 15 18 21 24 27 30 33 5 3 6 12 18 24 30 36 42 48 54 60 66 7.5 4.5 9 18 27 36 45 54 63 72 81 90 99 10 6 12 24 36 48 60 72 84 96 108 120 132 12.5 7.5 15 30 45 60 75 90 105 120 135 150 165 15 9 18 36 54 72 90 108 126 144 162 180 198 17.5 10.5 21 42 63 84 105 126 147 168 189 210 231 20 12 24 48 72 96 120 144 168 192 216 240 264 Dobutamine Injection USP Infusion Rate (mL/h) for 1000 mcg/mL concentration Drug Delivery Rate Patient Body Weight (kg) (mcg/kg/min) 5 10 20 30 40 50 60 70 80 90 100 110 0.5 0.1 0.3 0.6 0.9 1.2 1.5 1.8 2.1 2.4 2.7 3 3.3 1 0.3 0.6 1.2 1.8 2.4 3 3.6 4.2 4.8 5.4 6 6.6 2.5 0.7 1.5 3 4.5 6 7.5 9 10.5 12 13.5 15 16.5 5 1.5 3 6 9 12 15 18 21 24 27 30 33 7.5 2.2 4.5 9 13.5 18 22.5 27 31.5 36 40.5 45 49.5 10 3 6 12 18 24 30 36 42 48 54 60 66 12.5 3.7 7.5 15 22.5 30 37.5 45 52.5 60 67.5 75 82.5 15 4.5 9 18 27 36 45 54 63 72 81 90 99 17.5 5.2 10.5 21 31.5 42 52.5 63 73.5 84 94.5 105 115.5 20 6 12 24 36 48 60 72 84 96 108 120 132 Dobutamine Injection USP Infusion Rate (mL/h) for 2000 mcg/mL concentration Drug Delivery Rate Patient Body Weight (kg) (mcg/kg/min) 5 10 20 30 40 50 60 70 80 90 100 110 0.5 0.07 0.1 0.3 0.4 0.6 0.7 0.9 1 1.2 1.3 1.5 1.6 1 0.1 0.3 0.6 0.9 1.2 1.5 1.8 2.1 2.4 2.7 3 3.3 2.5 0.4 0.7 1.5 2 3 4 4.5 5 6 7 7.5 8 5 0.7 1.5 3 4.5 6 7.5 9 10.5 12 13.5 15 16.5 7.5 1.1 2.2 4.5 7 9 11 13.5 16 18 20 22.5 25 10 1.5 3 6 9 12 15 18 21 24 27 30 33 12.5 1.9 3.7 7 11 15 19 22.5 26 30 34 37.5 41 15 2.2 4.5 9 13.5 18 22.5 27 31.5 36 40.5 45 49.5 17.5 2.6 5.2 10.5 15.7 21 26.2 31.5 36.7 42 47.2 52.5 57.7 20 3 6 12 18 24 30 36 42 48 54 60 66 Concentrations of up to 5,000 mcg/mL have been administered to humans (250 mg/50 mL). The final volume administered should be determined by the fluid requirements of the patient. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.

CONTRAINDICATIONS Dobutamine Hydrochloride in 5% Dextrose Injection is contraindicated in patients with idiopathic hypertrophic subaortic stenosis and in patients who have shown previous manifestations of hypersensitivity to dobutamine. Solutions containing dextrose may be contraindicated in patients with known allergy to corn or corn products.

ADVERSE REACTIONS 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 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 patients: nausea, headache, anginal pain, nonspecific chest pain, palpitations, and shortness of breath. Isolated cases of thrombocytopenia have been reported. Administration of dobutamine hydrochloride, like other catecholamines, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels (see PRECAUTIONS). Longer-Term Safety − Infusions of up to 72 hours have revealed no adverse effects other than those seen with shorter infusions.

WARNINGS Increase in Heart Rate or Blood Pressure Dobutamine Hydrochloride in 5% Dextrose Injection 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 reverses these effects. Because dobutamine facilitates atrioventricular conduction, patients with atrial fibrillation are at risk of developing rapid ventricular response. Patients with preexisting hypertension appear to face an increased risk of developing an exaggerated pressor response. In patients who have atrial fibrillation with rapid ventricular response, a digitalis preparation should be used prior to institution of therapy with Dobutamine in D 5 W.

Ectopic Activity Dobutamine

Hydrochloride in 5% Dextrose Injection 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

Hydrochloride in 5% Dextrose Injection 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. Solutions containing dextrose should not be administered through the same administration set as blood, as this may result in pseudoagglutination or hemolysis. The intravenous administration of solutions may cause fluid overloading resulting in dilution of serum electrolyte concentrations, overhydration, congested states or pulmonary edema. The risk of dilutional states is inversely proportional to the electrolyte concentrations of the injections. The risk of solute overload causing congested states with peripheral and pulmonary edema is directly proportional to the electrolyte concentration of the injections. Excess administration of potassium-free solutions may result in significant hypokalemia.

PRECAUTIONS General During the administration of Dobutamine Injection, 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 hydrochloride. Hypovolemia should be corrected with suitable volume expanders before treatment with dobutamine hydrochloride 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 hydrochloride 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 hydrochloride does so.

Laboratory Tests

Dobutamine, like other β 2 -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 β-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, nitroglycerin, 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 hydrochloride, or its potential to affect fertility, have not been conducted.

Pregnancy Teratogenic

Effects −Reproduction studies performed in rats at doses up to the normal human dose (10 mcg/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 hydrochloride. 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 hydrochloride 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 hydrochloride is administered to a nursing woman. If a mother requires dobutamine hydrochloride treatment, breastfeeding should be discontinued for the duration of 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 infusion of dopamine.

Geriatric

Use Of the 1893 patients in clinical studies who were treated with dobutamine, 930 (49.1%) were 65 and older. No overall differences in safety or effectiveness were observed between these and younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or drug therapy.

Drug Interactions Animal studies indicate that dobutamine may be ineffective if the patient has recently received a ß-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.