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DOBUTamine Hydrochloride Injection

TABLE OF CONTENTS

1. DESCRIPTION 7. WARNINGS AND PRECAUTIONS
2. INDICATIONS AND USAGE 8. ADVERSE REACTIONS
3. DOSAGE AND ADMINISTRATION 9. OVERDOSAGE
4. CONTRAINDICATIONS 10. DRUG INTERACTIONS
5. MECHANISM OF ACTION 11. CLINICAL PHARMACOLOGY
6. USE IN SPECIFIC POPULATIONS 12. HOW SUPPLIED/STORAGE AND HANDLING

 

1. DESCRIPTION

DOBUTamine Injection, USP is 1,2-benzenediol, 4-[2-[[3-(4-hydro-xyphenyl)-1-methylpropyl]amino]ethyl]-hydrochloride, (±). It is a synthetic catecholamine. The structural formula is:

Molecular Formula: C18H23NO3 • HCl

Molecular Weight: 337.85

DOBUTamine Injection, USP is available in 20 mL and 40 mL single-dose vials for intravenous use only . Each mL contains: DOBUTamine hydrochloride, equivalent to 12.5 mg (41.5 mmol) DOBUTamine; 0.24 mg sodium metabisulfite (added during manufacture), and water for injection. pH adjusted between 2.5 to 5.5 with hydrochloric acid and/or sodium hydroxide. DOBUTamine is oxygen sensitive.

DOBUTamine is also available in 5% Dextrose Injection, USP. It is a sterile, nonpyrogenic, prediluted solution of DOBUTamine hydrochloride and dextrose in water for injection. It is administered by intravenous infusion.

Each 100 mL contains DOBUTamine hydrochloride equivalent to 50 mg, 100 mg, 200 mg, or 400 mg of DOBUTamine; dextrose, hydrous 5 g in water for injection, with sodium metabisulfite 25 mg and edetate disodium, dihydrate 10 mg added as stabilizers; osmolar concentration, respectively, 260, 263, 270, or 284 mOsmol/liter (calc.). The pH is 3.0 (2.5 to 5.5). May contain hydrochloric acid and/or sodium hydroxide for pH adjustment. DOBUTamine in 5% Dextrose Injection, USP is oxygen sensitive.

Dextrose, USP is chemically designated D-glucose monohydrate C6H12O6 • H2O, a hexose sugar freely soluble in water. It has the following structural formula:

The flexible plastic container is fabricated from a specially formulated CR3 plastic material. Water can permeate from inside the container into the overwrap but not in amounts sufficient to affect the solution significantly. Solutions in contact with the plastic container may leach out certain chemical components from the plastic in very small amounts; however, biological testing was supportive of the safety of the plastic container materials. Exposure to temperatures above 25°C/77°F during transport and storage will lead to minor losses in moisture content. Higher temperatures lead to greater losses. It is unlikely that these minor losses will lead to clinically significant changes within the expiration period.

2. INDICATIONS AND USAGE

DOBUTamine in 5% Dextrose Injection, USP is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of 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-AMPdependent 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-AMPdependent inotropes were consistently associated with increased risks of hospitalization and death. Patients with NYHA Class IV symptoms appeared to be at particular risk.

3. DOSAGE AND ADMINISTRATION

Do NOT add sodium bicarbonate or other alkalinizing substance, since DOBUTamine is inactivated in alkaline solution. DOBUTamine in 5% Dextrose Injection, USP is administered only intravenously via a suitable catheter or needle infusion. The less concentrated 0.5 mg/mL solution may be preferred when fluid expansion is not a problem. The more concentrated 1 mg/ mL, 2 mg/mL, or 4 mg/mL solutions may be preferred in patients with fluid retention or when a slower rate of infusion is desired.

Preparation and Stability of DOBUTamine Vials — At the time of administration, DOBUTamine injection must be further diluted in an IV container. Dilute 20 mL of DOBUTamine in at least 50 mL of diluent and dilute 40 mL of DOBUTamine in at least 100 mL of diluent. Use one of the following intravenous solutions as a diluent: Dextrose Injection 5%, Dextrose 5% and Sodium Chloride 0.45% Injection, Dextrose 5% and Sodium Chloride 0.9% Injection, Dextrose Injection 10%, 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, Sodium Chloride Injection 0.9%, 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 1.0 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. For the infusion rates necessary to achieve various delivery rates (mcg/kg/min) for patients of different weights, refer to the DOBUTamine Infusion Rate (mL/hr) charts below.

Rate of Administration: When administering DOBUTamine (or any potent medication) by continuous intravenous infusion, it is advisable to use a precision volume control I.V. set.

Each patient must be individually titrated to the desired hemodynamic response to DOBUTamine. The rate of administration and the duration of therapy should be adjusted according to the patient's response as determined by heart rate, presence of ectopic activity, blood pressure, urine flow, and, whenever possible, measurement of central venous or pulmonary wedge pressure and cardiac output. As with all potent intravenously administered drugs, care should be taken to control the rate of infusion so as to avoid inadvertent administration of a bolus of the drug.

Parenteral drug products should be visually inspected for particulate matter and discoloration prior to administration, whenever solution and container permit (see PRECAUTIONS).

Table 1: DOBUTamine Infusion Rate (mL/hr) Chart Using 500 mcg/mL Concentration

 

Table 2: DOBUTamine Infusion Rate (mL/hr) Chart Using 1000 mcg/mL Concentration

The rate of administration and the duration of therapy should be adjusted according to the patient’s response as determined by heart rate, presence of ectopic activity, blood pressure, urine flow, and, whenever possible, measurement of central venous or pulmonary wedge pressure and cardiac output.

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.

4. CONTRAINDICATIONS

DOBUTamine in 5% Dextrose Injection, USP is contraindicated in patients with idiopathic hypertrophic subaortic stenosis and in patients who have shown previous manifestations of hypersensitivity to DOBUTamine.

Dextrose solutions without electrolytes should not be administered simultaneously with blood through the same infusion set because of the possibility that pseudoagglutination of red cells may occur.

5. MECHANISM OF ACTION

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.

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.

6. USE IN SPECIFIC POPULATIONS

6.1 Usage in Pregnancy

Pregnancy Category B

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 2 times 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.

6.2 Labor and Delivery

The effect of DOBUTamine injection on labor and delivery is unknown.

6.3 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 treatment, breastfeeding should be discontinued for the duration of the treatment.

6.4 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.

6.5 Geriatric Use

Clinical studies of dobutamine injection did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. 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.

7. WARNINGS AND PRECAUTIONS

WARNINGS

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 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. 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 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 is instituted.

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.

No improvement may be observed in the presence of marked mechanical obstruction, such as severe valvular aortic stenosis.

Solutions containing dextrose should be used with caution in patients with known subclinical or overt diabetes mellitus.

Do not administer unless solution is clear and seal is intact.

If administration is controlled by a pumping device, care must be taken to discontinue pumping action before the container runs dry or air embolism may result.

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 ß2-agonists, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels. Accordingly, consideration should be given to monitoring serum potassium.

8. 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, 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.

9. OVERDOSAGE

Overdoses of DOBUTamine have been reported rarely. The following is provided to serve as a guide if such an overdose is encountered.

Signs and Symptoms

Toxicity from DOBUTamine hydrochloride is usually due to excessive cardiac b-receptor stimulation. The duration of action of DOBUTamine hydrochloride is generally short (T½ = 2 minutes) because it is rapidly metabolized by catechol-0- methyltransferase. The symptoms of toxicity may include anorexia, nausea, vomiting, tremor, anxiety, palpitations, headache, shortness of breath, and anginal and nonspecific chest pain. The positive inotropic and chronotropic effects of DOBUTamine on the myocardium may cause hypertension, tachyarrhythmias, myocardial ischemia, and ventricular fibrillation. Hypotension may result from vasodilation.

Treatment

To obtain up-to-date information about the treatment of overdose, a good resource is your certified Regional Poison Control Center. Telephone numbers of certified poison control centers are listed in the Physicians’ Desk Reference (PDR). In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drug kinetics in your patient.

The initial actions to be taken in a DOBUTamine hydrochloride overdose are discontinuing administration, establishing an airway, and ensuring oxygenation and ventilation. Resuscitative measures should be initiated promptly. Severe ventricular tachyarrhythmias may be successfully treated with propranolol or lidocaine. Hypertension usually responds to a reduction in dose or discontinuation of therapy.

Protect the patient’s airway and support ventilation and perfusion. If needed, meticulously monitor and maintain, within acceptable limits, the patient’s vital signs, blood gases, serum electrolytes, etc. If the product is ingested, unpredictable absorption may occur from the mouth and the gastrointestinal tract. Absorption of drugs from the gastrointestinal tract may be decreased by giving activated charcoal, which, in many cases, is more effective than emesis of lavage; consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal over time may hasten elimination of some drugs that have been absorbed. Safeguard the patient’s airway when employing gastric emptying or charcoal.

Forced diuresis, peritoneal dialysis, hemodialysis, or charcoal hemoperfusion have not been established as beneficial for an overdose of DOBUTamine hydrochloride.

10. DRUG INTERACTIONS

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. 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.

11. CLINICAL PHARMACOLOGY

Dobutamine hydrochloride is a direct-acting inotropic agent whose primary activity results from stimulation of the ß-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 one to two minutes; however, as much as ten minutes may be required to obtain the peak effect of a particular infusion rate.

The plasma half-life of dobutamine in humans is two 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-O-methyl dobutamine. The 3-O-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 Pediatric Use under Precautions).

Dextrose provides a source of calories. Dextrose is readily metabolized, may decrease losses of body protein and nitrogen, promotes glycogen deposition and decreases or prevents ketosis if sufficient doses are provided.

12. HOW SUPPLIED/STORAGE AND HANDLING

1) How Available:

a) Brand name: DOBUTREX (discontinued), by LILLY.

b) Generic drugs: DOBUTamine HYDROCHLORIDE, by various manufacturers.

2) How Supplied:

DOBUTamine Injection, USP vials (by HOSPIRA), 12.5 mg/mL is available as:

20 mL Single-Dose Vials containing 250 mg DOBUTamine (as the hydrochloride), boxes of 10 (List 2025).

40 mL Single-Dose Vials containing 500 mg DOBUTamine (as the hydrochloride), boxes of 10 (List 2025).

DOBUTamine Hydrochloride in 5% Dextrose Injection, USP in VIAFLEX Plus Plastic Containers ((by Baxter Healthcare Corp.) is supplied in the following:

2B0791 Dobutamine 250 mg/250 mL NDC 0338-1073-02

2B0792 Dobutamine 500 mg/250 mL NDC 0338-1075-02

2B0793 Dobutamine 1000 mg/250 mL NDC 0338-1077-02

2B0795 Dobutamine 250 mg/500 mL NDC 0338-1071-03

2B0796 Dobutamine 500 mg/500 mL NDC 0338-1073-03

3) Storage:

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.]

Rx only

Rev 09/2012