Dobutamine

DESCRIPTION

Dobutamine Injection, USP is 1,2-benzenediol, 4-[2-[[3-(4-hydro-xyphenyl)-1-methylpropyl]amino]ethyl]-hydrochloride, (±). It is a syntheticcatecholamine。

The clinical formulation is supplied in a sterile form for intravenous use only. Each mL contains: Dobutamine hydrochloride, equivalent to 12.5 mg (41.5 μmol) 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.

INDICATIONS

Dobutamine Injection, USP is indicated when parenteral therapy is necessary for inotropic support in the short-term treatment of adults with cardiac decompensation due to depressed contractility resulting either from organic heart disease or from cardiac surgical procedures.

In patients who have atrial fibrillation with rapid ventricular response, a digitalis preparation should be used prior to institution of therapy with dobutamine hydrochloride.

DOSAGE AND ADMINISTRATION

Note

Do not add Dobutamine Injection, USP to 5% Sodium Bicarbonate Injection or to any other strongly alkaline solution. Because of potential physical incompatibilities, it is recommended that dobutamine hydrochloride not be mixed with other drugs in the same solution. Dobutamine hydrochloride 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 Injection, USP must be further diluted in an intravenous container to at least a 50 mL solution using one of the following intravenous solutions as a diluent: 5% Dextrose Injection, USP; 5% Dextrose and 0.45% Sodium Chloride Injection, USP; 5% Dextrose and 0.9% Sodium Chloride Injection, USP; 10% Dextrose Injection, USP; 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, USP; or Sodium Lactate Injection, USP. Intravenous solutions should be used within 24 hours.

Recommended Dosage

The rate of infusion needed to increase cardiac output usually ranged from 2.5 to 15 mcg/kg/min (see Table 1). On rare occasions, infusion rates up to 40 mcg/kg/min have been required to obtain the desired effect.

Table 1 Dobutamine Infusion Rate (mL/kg/min) for Concentrations of 250, 500, and 1,000 mcg/mL

Drug Delivery Rate	Infusion Delivery Rate
	250 mcg/mL*	500 mcg/mL†	1,000 mcg/mL‡
(mcg/kg/min)	(mL/kg/min)	(mL/kg/min)	(mL/kg/min)
2.5	0.01	0.005	0.0025
5	0.02	0.01	0.005
7.5	0.03	0.015	0.0075
10	0.04	0.02	0.01
12.5	0.05	0.025	0.0125
15	0.06	0.03	0.015
*250 mcg/mL of diluent †500 mcg/mL or 250 mg/500 mL of diluent ‡1,000 mcg/mL or 250 mg/250 mL of diluent

Rates of infusion in mL/h for Dobutamine concentrations of 500 mcg/mL, 1,000 mcg/mL, and 2,000 mcg/mL are given in Table 2.

Table 2
多巴酚丁胺正usion Rate (mL/h) for 500 mcg/mL concentration

Drug Delivery Rate (mcg/kg/min)	多巴酚丁胺正usion Rate (mL/h) for 500 mcg/mL concentration Patient Body Weight (kg)
	30	40	50	60	70	80	90	100	110
2.5	9	12	15	18	21	24	27	30	33
5	18	24	30	36	42	48	54	60	66
7.5	27	36	45	54	63	72	81	90	99
10	36	48	60	72	84	96	108	120	132
12.5	45	60	75	90	105	120	135	150	165
15	54	72	90	108	126	144	162	180	198
Drug Delivery Rate (mcg/kg/min)	多巴酚丁胺正usion Rate (mL/h) for 1,000 mcg/mL concentration Patient Body Weight (kg)
	30	40	50	60	70	80	90	100	110
2.5	4.5	6	7.5	9	10.5	12	13.5	15	16.5
5	9	12	15	18	21	24	27	30	33
7.5	13.5	18	22.5	27	31.5	36	40.5	45	49.5
10	18	24	30	36	42	48	54	60	66
12.5	22.5	30	37.5	45	52.5	60	67.5	75	82.5
15	13.5	18	22.5	27	31.5	36	40.5	45	49.5

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.

HOW SUPPLIED

DobutamineInjection, USP is supplied in 20 mL single-dose glass vials containing 250 mg dobutamine, as the hydrochloride as follows:

Unit of Sale	Concentration	Each
NDC 0409-2344-01 Carton containing 1 Vial	250 mg/20 mL (12.5 mg/mL)	NDC0409-2344-01 20 mL Single-Dose Vial
NDC 0409-2344-02 Tray containing 10 Vials	250 mg/20 mL (12.5 mg/mL)	NDC0409-2344-62 20 mL Single-Dose Vial

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

Distributed by Hospira, Inc., Lake Forest, IL 60045 USA. Revised: N/A

SIDE EFFECTS

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警告regarding exaggerated chronotropic and pressor effects).

Approximately 5% of patients have had increased premature ventricular beats during infusions.

These effects are dose related.

Hypotension

血压的急剧减少偶而ionally 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 (seePRECAUTIONS).

Longer-Term Safety

Infusions of up to 72 hours have revealed no adverse effects other than those seen with shorter infusions.

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.

警告

Dobutamine hydrochloride 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 hydrochloride facilitates atrioventricular conduction, patients with atrial fibrillation are at risk of developing rapid ventricular response. Patients with pre-existing hypertension appear to face an increased risk of developing an exaggerated pressor response.

Dobutamine hydrochloride may precipitate or exacerbate ventricular ectopic activity, but it rarely has caused ventricular tachycardia.

Reactions suggestive of hypersensitivity associated with administration of Dobutamine Injection, USP, including skin rash, fever, eosinophilia, and bronchospasm, have been reported occasionally.

1. Increase in Heart Rate or Blood Pressure
2. Ectopic Activity
3. Hypersensitivity
4. Dobutamine Injection, USP contains sodium metabisulfite, 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.

PRECAUTIONS

General

1. During the administration of Dobutamine Injection, USP, 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.
2. Hypovolemia should be corrected with suitable volume expanders before treatment with dobutamine hydrochloride is instituted.
3. 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 β₂-agonists, can produce a mild reduction in serum potassium concentration, rarely to hypokalemic levels. Accordingly, consideration should be given to monitoring serum potassium.

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

生殖研究在大鼠进行剂量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.

儿童使用

The safety and effectiveness of Dobutamine Injection, USP for use in pediatric patients have not been studied.

OVERDOSE

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 is usually due to excessive cardiac β-receptor stimulation. The duration of action of dobutamine is generally short (T_1/2= 2 minutes) because it is rapidly metabolized by catechol-O-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 thePhysicians' Desk Reference (PDR)。In managing overdosage, consider the possibility of multiple drug overdoses, interaction among drugs, and unusual drugkineticsin your patient.

The initial actions to be taken in a dobutamine overdose are discontinuing administration, establishing an airway, and ensuringoxygenationandventilation。Resuscitative measures should be initiated promptly. Severeventriculartachyarrhythmias may be successfully treated with propranolol or lidocaine.Hypertensionusually responds to a reduction in dose or discontinuation of therapy.

Protect the patient's airway and support ventilation andperfusion。如果需要,精心监视和维护,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 thegastrointestinal tract。Absorption of drugs from thegastrointestinaltract may be decreased by givingactivated charcoal, which, in many cases, is more effective thanemesisor lavage; consider charcoal instead of or in addition togastricemptying. 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.

Forceddiuresis,peritoneal dialysis,hemodialysis, or charcoal hemo-perfusion have not been established as beneficial for an overdose of dobutamine.

CONTRAINDICATIONS

Dobutamine hydrochloride is contraindicated in patients withidiopathichypertrophicsubaortic stenosisand in patients who have shown previous manifestations of hypersensitivity to Dobutamine Injection, USP solution.

CLINICAL PHARMACOLOGY

Dobutamine hydrochloride is a direct-actinginotropicagent whose primary activity results from stimulation of the β receptors of the heart while producing comparatively mild chronotropic,hypertensive, arrhythmogenic, and vasodilative effects. It does not cause the release ofendogenousnorepinephrine, as doesdopamine。In animal studies, dobutamine hydrochloride produces less increase in heart rate and less decrease in peripheralvascularresistance for a given inotropic effect than does isoproterenol.

In patients with depressed cardiac function, both dobutamine hydrochloride and isoproterenol increase thecardiac outputto a similar degree. In the case of dobutamine hydrochloride, this increase is usually not accompanied by marked increases in heart rate (althoughtachycardiais occasionally observed), and the cardiacstroke volumeis usually increased. In contrast, isoproterenol increases thecardiac indexprimarily by increasing the heart rate whilestrokevolume changes little or declines.

Facilitation ofatrioventricularconduction has been observed in human electrophysiologic studies and in patients withatrial fibrillation。

Systemic vascular resistance is usually decreased with administration of dobutamine hydrochloride. Occasionally, minimumvasoconstrictionhas been observed.

Most clinical experience with dobutamine hydrochloride isshort-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 hydrochloride in humans is 2 minutes. The principal routes ofmetabolismare 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 ortricyclic antidepressantsdoes not alter the actions of dobutamine in animals, which indicates that the actions of dobutamine hydrochloride are not dependent on presynaptic mechanisms.

PATIENT INFORMATION

No information provided. Please refer to the警告andPRECAUTIONSsections.