DBL™ Dobutamine Hydrochloride

New Zealand - English - Medsafe (Medicines Safety Authority)

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Active ingredient:
Dobutamine hydrochloride 12.5 mg/mL;  ;  
Available from:
Pfizer New Zealand Limited
INN (International Name):
Dobutamine hydrochloride 12.5 mg/mL
Dosage:
12.5 mg/mL
Pharmaceutical form:
Solution for injection
Composition:
Active: Dobutamine hydrochloride 12.5 mg/mL     Excipient: Sodium metabisulfite Water for injection
Units in package:
Vial, 1x20ml, 20 mL
Class:
Prescription
Prescription type:
Prescription
Manufactured by:
Abbott Laboratories Inc
Product summary:
Package - Contents - Shelf Life: Vial, 20ml - 1 dose units - 24 months from date of manufacture stored at or below 25°C
Authorization number:
TT50-5095
Authorization date:
1991-06-26

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NEW ZEALAND DATA SHEET

1.

PRODUCT NAME

DBL™ Dobutamine Hydrochloride Injection

2.

QUALITATIVE AND QUANTITATIVE COMPOSITION

Dobutamine Hydrochloride Injection is a sterile solution containing in each 20 mL

vial, Dobutamine Hydrochloride USP 280.2

mg (250 mg Dobutamine equivalent) and

Sodium Metabisulfite BP 4.4 mg.

Excipient(s) with known effect

Sodium Metabisulfite

For the full list of excipients, see section 6.1.

3.

PHARMACEUTICAL FORM

Solution for injection

Dobutamine hydrochloride is a white to practically white, crystalline powder. It is sparingly

soluble in water and methyl alcohol; soluble in alcohol.

4.

CLINICAL PARTICULARS

4.1 Therapeutic indications

Dobutamine hydrochloride is indicated when inotropic support is necessary for the treatment

patients

with

hypoperfusion

states

whom

cardiac

output

insufficient

meet

circulatory demands. Dobutamine hydrochloride is also indicated when inotropic support is

required for the treatment of patients in whom abnormally increased ventricular filling

pressures introduce the risk of pulmonary congestion and oedema. Conditions which may

precipitate such situations include the following hypoperfusion states:

Initially cardiac in origin

A. Acute heart failure

Acute myocardial infarction

Cardiogenic shock

Following cardiac surgery

Medicine-induced depression of cardiac contractility such as that which occurs in

excessive β-adrenergic receptor blockade.

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B. Chronic heart failure

Acute decompensation of chronic congestive heart failure

Temporary inotropic support in advanced chronic congestive heart failure, as an

adjunct to therapy with conventional oral inotropic agents, systemic vasodilators, and

diuretics.

Initially noncardiac in origin

Acute hypoperfusion states secondary to trauma, surgery, sepsis, or hypovolaemia

when mean arterial pressure is above 70-mm Hg and pulmonary capillary wedge

pressure is 18-mm Hg or greater, with inadequate response to volume repletion and

increased ventricular filling pressure

Low cardiac output secondary to mechanical ventilation with positive end-expiratory

pressure (PEEP).

Dobutamine hydrochloride may be used as a substitute for physical exercise in stress testing

in the diagnosis of coronary artery disease. When dobutamine hydrochloride is used for this

purpose, as is the case when exercise is used for stress testing, patients should be informed of

the potential risks involved in the test. In addition, patients should be subjected to the same

close monitoring that is mandatory in standard exercise stress tests, including continuous

electrocardiographic monitoring.

4.2 Dose and method of administration

Administration

Because

short

half-life,

dobutamine

hydrochloride

must

administered

continuous intravenous infusion. Following the initiation of a constant rate infusion, or upon

changing

rate,

steady-state

dobutamine

plasma

concentration

achieved

within

approximately 10 minutes. Thus, loading doses or bolus injections are not necessary and are

not recommended.

Recommended Dosage

The rate of infusion needed to increase cardiac output has ranged from 2.5 to 10 mcg/kg/min

in the majority of patients. Frequently, doses up to 20 mcg/kg/min are required for adequate

haemodynamic improvement. On rare occasions, infusion rates up to 40 mcg/kg/min have

been reported.

The rate of administration and the duration of therapy should be adjusted according to the

patient's

response,

determined

following

clinical

indicators:

haemodynamic

parameters such as heart rate and rhythm, arterial pressure, and, whenever possible, cardiac

output and measurements of ventricular filling pressures (central venous, pulmonary capillary

wedge, and left atrial), and signs of pulmonary congestion and organ perfusion (urine flow,

skin temperature, and mental status).

Concentrations up to 5,000 mg/L have been administered to humans (250 mg/50 mL). The

final volume administered should be determined by the fluid requirements of the patient.

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Rather

than

abruptly

discontinuing

therapy

with

dobutamine

hydrochloride,

often

advisable to decrease the dosage gradually.

Dosage Units

Most reports on dobutamine hydrochloride have expressed the dose in relation to body mass,

for example, mcg/kg/min. This practice is useful to relate doses in infants and children to

those in adults. Among adults, body mass has little influence on the effect of dobutamine

hydrochloride; since the dosage of dobutamine hydrochloride should be titrated in each

patient, adults may be as easily dosed with mcg/min units. The dosage of dobutamine

hydrochloride may be initiated at 100 to 200 mcg/min and increased gradually to 1000 to

2000 mcg/min or greater, depending on the clinical and haemodynamic response of the

individual patient.

Rates of Infusion Based on Concentration of Dobutamine Hydrochloride

The rates of fluid infusion that are required to deliver specific dosages are a function of the

concentration of dobutamine hydrochloride in the infusate. The following table provides a

guideline of infusion rates (mL/kg/min) required for 3 frequently used concentrations of

dobutamine hydrochloride (250, 500, and 1000 mg/L) in order to deliver the medicine

dosages (mcg/kg/min) which are indicated in the left hand column of the table.

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Medicine Delivery Rate

(mcg/kg/min)

Infusion Delivery Rate

250 mg/L *

(mL/kg/min)

500 mg/L †

(mL/kg/min)

1000 mg/L ‡

(mL/kg/min)

0.01

0.005

0.0025

0.02

0.01

0.005

0.03

0.015

0.0075

0.04

0.02

0.01

12.5

0.05

0.025

0.0125

0.06

0.03

0.015

* 250 mg/L of diluent

† 500 mg/L or 250 mg/500 mL of diluent

‡ 1000 mg/L or 250 mg/250 mL of diluent

Dobutamine Hydrochloride Injection when diluted to 250 micrograms/mL and 500

micrograms/mL with 0.9% Sodium Chloride Injection and 5% Glucose Injection, was found

to be stable for 24 hours at room temperature and in the presence of fluorescent light.

4.3 Contraindications

Dobutamine

hydrochloride

contraindicated

patients

have

shown

previous

manifestations of hypersensitivity to dobutamine hydrochloride.

4.4 Special warnings and precautions for use

Increase in Heart Rate or Arterial Blood Pressure

Dobutamine hydrochloride may cause an increase in heart rate or blood pressure, especially

in systolic pressure. Approximately 10% of the patients in clinical studies have had rate

increments of 30 beats/min or more, and about 7.5% have had a 50-mm Hg or greater

increase in systolic pressure. Reduction of dosage usually reverses these effects promptly.

Patients with pre-existing hypertension are more likely to develop an exaggerated pressor

response.

Increased Atrioventricular Conduction

Because dobutamine hydrochloride facilitates atrioventricular conduction, patients with atrial

flutter or fibrillation may develop rapid ventricular responses.

Ventricular Tachyarrhythmias

Dobutamine hydrochloride may precipitate or exacerbate ventricular ectopic activity; rarely

has it caused ventricular tachycardia or fibrillation.

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Impaired Ventricular Filling and Ventricular Outflow Obstruction

Inotropic agents, including dobutamine hydrochloride, do not improve haemodynamics in

most patients with mechanical obstruction that hinders either ventricular filling or outflow, or

both. Inotropic response may be inadequate in patients with markedly reduced ventricular

compliance. Such conditions are present in cardiac tamponade, valvular aortic stenosis, and

idiopathic hypertrophic subaortic stenosis. Beneficial inotropic effects may be seen in some

patients if the heart is dilated or under excessive effect of β-adrenergic receptor antagonists.

Hypersensitivity

Reactions suggestive of hypersensitivity associated with the administration of dobutamine

hydrochloride,

including

skin

rash,

fever,

oeosinophilia,

bronchospasm,

have

been

reported occasionally.

Allergic Reaction

Dobutamine Hydrochloride 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.

General

During

administration

dobutamine

hydrochloride,

with

parenteral

catecholamine, heart rate and rhythm, arterial blood pressure, and infusion rate should be

monitored closely. When initiating therapy, electrocardiographic monitoring is advisable

until a stable response is achieved.

Hypovolaemia

should

corrected

before

treatment

with

dobutamine

hydrochloride

instituted.

No improvement may be observed in the presence of marked mechanical obstruction, such as

severe valvular aortic stenosis.

Usage for Heart Failure Complicating an Acute Myocardial Infarction

Although the treatment of heart failure and the reduction in cardiac diameter will decrease

myocardial oxygen consumption, there is still concern that the use of any inotropic agent may

increase myocardial oxygen demand and the size of an infarction by intensifying ischaemia.

Clinical

experimental

evidence

with

dobutamine

hydrochloride

following

acute

myocardial infarction suggests that dobutamine hydrochloride does not have an adverse

effect on the myocardium when used in doses that do not cause excessive increments in heart

rate or arterial pressure. The dose of dobutamine hydrochloride should be titrated to prevent

an excessive increase in heart rate and systolic blood pressure.

Usage in Hypotension

When hypotension is largely attributable to decreased cardiac output and coincides with an

elevated ventricular filling pressure, the infusion of dobutamine hydrochloride may help

restore the pressure.

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As volume is replenished in the treatment of acute hypoperfusion states and there is an

increase in pulmonary wedge or central venous pressures but with no increase in cardiac

output and arterial pressure, dobutamine hydrochloride may improve output and help restore

the arterial pressure.

In general, when mean arterial blood pressure is less than 70-mm Hg in the absence of an

increased ventricular filling pressure, hypovolaemia may be present and would require

treatment with appropriate volume repleting solutions before dobutamine hydrochloride is

given.

If arterial blood pressure remains low or decreases progressively during administration of

dobutamine hydrochloride despite adequate ventricular filling pressure and cardiac output,

consideration may be given to the concomitant use of a peripheral vasoconstrictor agent such

as dopamine or norepinephrine.

Paediatric population

Dobutamine hydrochloride has been administered to children with low-output hypoperfusion

states resulting from decompensated heart failure, cardiac surgery, and cardiogenic and septic

shock.

Some

haemodynamic

effects

dobutamine

hydrochloride

quantitatively or qualitatively different in children as compared to adults ( see section 5.1).

Increments in heart rate and blood pressure appear to be more frequent and intense in

children. Pulmonary wedge pressure may not decrease in children, as it does in adults, or it

may actually increase, especially in infants less than one year old. Accordingly, the use of

dobutamine hydrochloride in children should be monitored closely, bearing in mind these

pharmacodynamic characteristics.

4.5 Interaction with other medicines and other forms of interaction

The potency of dobutamine hydrochloride may be decreased if the patient is given β-

adrenergic

receptor

antagonists.

such

case,

unopposed

α-agonist

effects

dobutamine hydrochloride may become apparent, including peripheral vasoconstriction and

hypertension. Conversely, α-adrenergic blockade may make the β-1 and β-2 effects apparent,

resulting in tachycardia and vasodilatation.

There has been no overt indication of medicine interactions in clinical studies in which

dobutamine hydrochloride was administered concurrently with other medicines, including

digitalis

preparations,

furosemide,

spironolactone,

lidocaine,

nitroglycerin,

nitroprusside,

isosorbide dinitrate, morphine, atropine, heparin, protamine, potassium chloride, folic acid,

and acetaminophen. Pharmacodynamic interactions with dopamine and vasodilators are

described in the see section 5.1.

Laboratory Test

Dobutamine, like other β

-agonists, can produce a mild reduction in serum potassium

concentration, rarely to hypokalaemic levels. Accordingly, consideration should be given to

monitoring serum potassium.

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4.6 Fertility, pregnancy and lactation

Fertility

No data available.

Pregnancy

Reproduction studies performed in rats at doses up to 3.5 times 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 foetus or teratogenic effects

due to dobutamine hydrochloride. Since there are no adequate and well-controlled studies in

pregnant women, and since animal reproduction studies are not always predictive of human

response, dobutamine hydrochloride should not be used during pregnancy unless the potential

benefits outweigh the potential risks to the foetus.

Lactation

It is not known whether this medicine is excreted in human milk. Because many medicines

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.

4.7 Effects on ability to drive and use machinery

Dobutamine Hydrochloride Injection may be likely to produce minor or moderate

adverse effects that may impair the patient's ability to concentrate and react and therefore

constitute a risk in the ability to drive and use machines.

4.8 Undesirable effects

Heart Rate, Blood Pressure, and Ventricular Ectopic Activity

A 10- to 20-mm Hg increase in systolic blood pressure and an increase in heart rate of 5 to 15

beats/minute have been noted in many patients ( see section 4.4). Approximately 5% of

patients have had increased premature ventricular beats during infusions of dobutamine

hydrochloride. These effects are usually 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.

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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 hypokalaemic levels ( see section 4.4).

Long-Term Safety

Infusions for up to 72 hours have revealed no adverse effects other than those seen with

shorter infusions. There is evidence that partial tolerance develops with continuous infusions

of dobutamine hydrochloride for 72 hours or more; therefore, higher doses may be required

to maintain the same effects.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicine is important. It

allows

continued

monitoring

benefit/risk

balance

medicine.

Healthcare

professionals

asked

report

suspected

adverse

reactions

https://nzphvc.otago.ac.nz/reporting/.

4.9 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 hydrochloride is usually due to excessive cardiac β-receptor

stimulation. The duration of action of dobutamine hydrochloride is generally short (T

minutes) because it is rapidly metabolised 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

dobutamine

myocardium

cause

hypertension,

tachyarrhythmias, myocardial ischaemia, and ventricular fibrillation. Hypotension may result

from vasodilation. If the product is ingested, unpredictable absorption may occur from the

mouth and the gastrointestinal tract.

Treatment

In managing overdosage, consider the possibility of multiple medicine overdoses, interaction

among medicines, and unusual medicine kinetics in your patient.

The initial actions to be taken in a dobutamine hydrochloride overdose are discontinuing

administration,

establishing

airway,

ensuring

oxygenation

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.

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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. Absorption of medicines from the gastrointestinal tract may be decreased by

giving activated charcoal, which, in many cases, is more effective than emesis or lavage;

consider charcoal instead of or in addition to gastric emptying. Repeated doses of charcoal

over time may hasten elimination of some medicines that have been absorbed. Safeguard the

patient's airway when employing gastric emptying or charcoal.

Forced diuresis, peritoneal dialysis, haemodialysis, or charcoal haemoperfusion have not

been established as beneficial for an overdose of dobutamine hydrochloride.

For advice on the management of overdose please contact the National Poisons Centre on

0800 POISON (0800 764766).

5.

PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Mechanism of action

Dobutamine hydrochloride is a direct acting inotropic agent whose primary activity results

from

stimulation

cardiac

adrenergic

receptors;

produces

comparatively

mild

chronotropic,

hypertensive,

arrhythmogenic,

vasodilator

effects.

contrast

with

dopamine,

does

release

norepinephrine

actions

dependent

norepinephrine stores in the heart.

In animal studies, dobutamine hydrochloride produces less increase in heart rate and less

decrease in peripheral vascular resistance for a given inotropic effect than does isoproterenol.

In humans, dobutamine hydrochloride increases stroke volume and cardiac output and

decreases ventricular filling pressure and total systemic and pulmonary vascular resistances.

The ventricular function curve is shifted upwards and to the left as a reflection of increased

myocardial contractility.

Heart rate is not increased significantly by the usual dosage of dobutamine hydrochloride;

however,

significant

tachycardia

occur

with

high

doses

(usually

greater

than

mcg/kg/min).

Arterial blood pressure usually is not changed significantly by dobutamine hydrochloride

because the effect of the increase in cardiac output is balanced by the concomitant decrease in

peripheral vascular resistance. Both increments and decrements in arterial blood pressure

have been reported. Patients with pre-existing arterial hypertension, even those who are

normotensive at the time, seem more susceptible to sustaining a pressor response.

In animals, dobutamine hydrochloride has been shown to decrease pulmonary hypoxic

vasoconstriction. This may result in increased perfusion of poorly ventilated areas. This effect

may decrease arterial oxygen saturation in some patients, but to a lesser extent than with

dopamine or isoproterenol. Due to the increased cardiac output in such patients, oxygen

transport is generally increased by dobutamine hydrochloride. Dobutamine hydrochloride has

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been shown to prevent or to revert partially the decrease in cardiac output that occurs in

patients during mechanical ventilation with positive end-expiratory pressure (PEEP).

Dobutamine hydrochloride does not act at dopamine receptors; thus it does not selectively

dilate renal or splanchnic vessels. Dobutamine hydrochloride may improve renal blood flow,

glomerular filtration rate, urine flow, and sodium excretion by increasing cardiac output and

by nonselective vasodilatation.

Dobutamine hydrochloride also exhibits inotropic effects in children, but the haemodynamic

response is somewhat different than that in adults. Although cardiac output increases in

children, there is a tendency for systemic vascular resistance and ventricular filling pressure

to decrease less and for heart rate and arterial blood pressure to increase more in children than

adults.

Pulmonary

wedge

pressure

increase

during

infusion

dobutamine

hydrochloride in children 12 months of age or younger.

Facilitation

atrioventricular

conduction

been

observed

during

administration

dobutamine hydrochloride in human electrophysiologic studies and in patients with atrial

fibrillation.

Like

inotropic

agents,

dobutamine

hydrochloride

increases

myocardial

oxygen

consumption. Dobutamine hydrochloride also increases coronary blood flow and myocardial

oxygen supply. The changes in oxygen demand are dependent on several factors, including

the following: (a) changes in ventricular diameter, which, in turn, determines the level of wall

tension required to generate intraventricular pressure during systole; (b) changes in afterload,

generally proportional to changes in systolic blood pressure; and (c) changes in heart rate.

When the use of an inotropic agent in a patient with a failing, dilated heart results in a

decrease in ventricular diameter, oxygen demand may increase only slightly or not at all,

provided

afterload

heart

rate

increase

markedly.

general,

dobutamine

hydrochloride does not cause an imbalance between oxygen consumption and supply in either

animals or humans with heart disease. Increments in oxygen delivery have often exceeded the

augmentation in oxygen uptake during infusion of dobutamine hydrochloride, so that oxygen

saturation in coronary sinus blood increases. The arteriovenous extraction ratio of lactic acid,

an indirect evidence of unimpeded aerobic metabolism, is generally maintained during

administration of dobutamine hydrochloride. In some instances, myocardial lactate extraction

has decreased. Net lactate production has been reported in a few patients; this has occurred

especially when heart rate and/or arterial blood pressure have increased excessively during

infusion of dobutamine hydrochloride, or when ventricular dysfunction was not present prior

to the administration of dobutamine hydrochloride.

In patients with angina pectoris who do not have heart failure, infusions of dobutamine

hydrochloride have mimicked the effects of physical exercise, increasing myocardial oxygen

demand in excess of coronary oxygen supply, and thereby producing reversible clinical signs

of myocardial ischaemia. These signs have included anginal pain, ST segment depression,

thallium scintigraphic perfusion defects, and new wall motion abnormalities.

Myocardial infarct size and the incidence and severity of ventricular arrhythmias were not

increased in patients with acute myocardial infarction who were treated with dobutamine

hydrochloride for 24 hours, as compared to similar patients who did not receive dobutamine

hydrochloride. In animals, administration of dobutamine hydrochloride shortly after the

ligation of coronary arteries reduces infarct size, when compared to controls receiving saline

solution

dopamine.

other

animals

with

experimental

infarction

were

given

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