Dobutamin Admeda 250
Добутамин Адмеда 250
SUMMARY OF PRODUCT CHARACTERISTICS
Резюме качества продукта
1. Name Of The Medicinal Product
Dobutamin Admeda 250
2. Qualitative And Quantitative Composition
1 ampoule Dobutamin Admeda 250 contains 250 mg dobutamine as dobutamine
hydrochloride (280 mg) in 50 ml solution for intravenous infusion.
For excipients, see 6.1
3. Pharmaceutical Form
Solution for intravenous infusion
4. Clinical Particulars
4.1. Therapeutic indications
For inotropic support in the treatment of low output cardiac
failure associated with myocardial infarction, open heart surgery, cardiomyopathies,
septic shock and cardiogenic shock.
4.2. Posology and method of administration
Dobutamine dosage must be adjusted individually according to
the response of the patient and the occurrence of side effects. The
duration of infusion will depend on the circumstances of each individual
case. Tolerance may develop with continuous infusion of dobutamine for
72 hours or more, which may necessitate an increase in dosage. It is
recommended that the dosage is reduced gradually before discontinuing
Dosing in Adults:
Most adult patients will respond satisfactorily to dosages of 2.5 to
10 µg/kg/min. Dosages of up to 40 µg/kg/min have been administered
in individual cases.
Dosing in Children:
Dosages between 1 and 15 µg/kg/min have been used. There is evidence
that the minimum effective dosage is higher in children than in adults.
Caution is advised at higher dosages, as there is also evidence that
the maximum tolerable dosage is lower in children than in adults. Most
side effects, and especially tachycardia, are observed at doses of >
7.5 µg/kg/min. The dosage in children should therefore be titrated
carefully to take into account of the apparently narrower therapeutic
Tables showing the infusion rates for different dosages
for different initial concentrations:
Dosages for infusion pumps:
1 injection vial of 250 mg dobutamine in 50 ml solution
||Rate in ml/hour
Dosages for continuous infusion apparatus:
1 injection vial of 250 mg dobutamine to 500 ml solution volume
||Rate in ml/hour
* If the concentration is doubled (i.e., 2 x 250 mg
dobutamine to 500 ml of solution volume, or 250 mg dobutamine to 250
ml of solution volume), then the infusion rate should be halved.
Method of Administration:
Dobutamin Admeda is presented in 50 ml for use undiluted in constant
infusion pumps. Alternatively it can be further diluted before administration.
Suitable diluents include: 5 % glucose solution, physiological saline
solution, or Ringer lactate solution.
To be used only for intravenous infusion. Due to its
short half-life, dobutamine must be administered as a continuous intravenous
infusion. After dilution, dobutamine is administered through an intravenous
needle or catheter using a giving-set which incorporates a drip-chamber
or other dose-metering device. High concentrations of dobutamine should
only be given with an infusion pump, to ensure accurate dosage.
Dobutamine is contra-indicated in patients with
Known hypersensitivity to dobutamine or
to any of the excipients
severe hypovolaemic states,
mechanical obstruction that hinders ventricular filling
and/or outflow (such as pericardial tamponade, constrictive pericarditis,
hypertrophic obstructive cardiomyopathy/idiopathic hypertrophic sub-aortic
stenosis and severe valvular aortic stenosis)
concomitant administration of mono-amine oxidase inhibitors
4.4. Special warnings and special precautions
Hypovolaemia should be corrected before treatment with dobutamine
Cardiac rate and rhythm, blood pressure, urine flow and infusion rate
must be monitored closely during administration of dobutamine. If possible,
cardiac output, central venous pressure and pulmonary wedge pressure
should be monitored continuously. In the event of an unwanted increase
in heart rate or systolic blood pressure, or if an arrhythmia is precipitated,
the dose of dobutamine should be reduced or the drug discontinued temporarily.
Generally, the use of dobutamine in patients with myocardial ischaemia
should be determined on a case-by-case basis. A deterioration of clinical
symptoms may occur in patients with severe coronary heart disease, especially
if dobutamine therapy is accompanied by a substantial rise in heart
rate and/or blood pressure.
Patients with atrial fibrillation or atrial flutter should be digitalised
before dobutamine therapy. Patients with hypertension are at increased
risk of an exaggerated increase in blood pressure. A slight reduction
in serum potassium may occur so monitoring levels should be considered.
Angina pectoris, tachy- and bradycardia, arrhythmias, hyper- and hypotension
have been reported during dobutamine stress echocardiography. In rare
cases serious cardiovascular adverse events including transmural ischemia,
myocardial infarction, and heart arrest may occur.
4.5. Interaction with other medicinal products
and other forms of interaction
Concomitant or preceeding therapy with ß-blockers may
attenuate or reverse the positive inotropic effect of dobutamine. As
a consequence, a -effects will predominate which can lead to peripheral
vasoconstriction, resulting in a rise in blood pressure. The magnitude
of this interaction depends on the type and duration of the ß-receptor
In case of concomitant a -receptor blockade, the dominating ß-mimetic
effects can lead to additional tachycardia and peripheral vasodilation.
Concomitant use of dobutamine and predominantly venously acting vasodilators
(e.g. nitrates, sodium nitroprusside) may result in a higher cardiac
output and lower peripheral vascular resistance and ventricular filling
pressure than seen when either agent is used alone.
The concomitant administration of ACE inhibitors (e.g. captopril) and
high doses of dobutamine can lead to a rise in cardiac output accompanied
by increased myocardial oxygen consumption. The occurrence of chest
pain and arrhythmias has been reported with this combination.
Combination of dobutamine with dopamine leads to a more marked increase
in blood pressure (as a function of the dopamine dosage); the ventricular
filling pressure falls or remains unchanged.
As the administration of dobutamine can increase insulin requirements
in diabetic patients their glucose level should be checked at the start
of dobutamine therapy, on changing the infusion rate and on discontinuing
the infusion. If necessary, the insulin dosage should be adjusted accordingly.
The concomitant administration of MAO inhibitors is contraindicated
as they can lead to life-threatening side effects, such as hypertensive
crises, cardiovascular failure, arrhythmias and intracranial bleeding.
4.6. Pregnancy and lactation
Animal studies have shown no evidence of teratogenic effects
with dobutamine. There are no adequate studies in pregnant or breast
feeding women. Following one case of short-term administration during
the 18th week of pregnancy, a healthy child was born.
Dobutamine should only be used in pregnant women if the expected benefits
outweigh the potential risk to the foetus. Breast-feeding should be
interrupted if treatment is necessary.
4.7. Effects on ability to drive and use machines
4.8. Undesirable effects
Many side effects are dose related but are infrequent at dosages
below 7.5 µg/kg/min. Dobutamine may cause a marked increase in
heart rate or blood pressure, especially systolic pressure. At therapeutic
dosages, heart rate increases by 5 - 15 beats/min in most patients and
by 30 beats/min or more in 10% of patients. Similarly, systolic pressure
rises by 10-20 mmHg in most patients and by 50 mmHg or greater in 7.5%
of patients. Patients with existing arterial hypertension develop greater
increases in blood pressure.
Dobutamine can precipitate or exacerbate ventricular arrhythmias; for
example, a dose-dependent increase in ventricular extrasystoles has
been observed in 5% of patients receiving dobutamine infusion. Ventricular
tachycardia or fibrillation occur rarely. Bradycardia has been reported
As dobutamine shortens AV conduction time, patients with atrial fibrillation
or atrial flutter are at risk of developing increased ventricular rate.
Precipitous falls in blood pressure have been reported occasionally;
decreasing the dose or discontinuing the infusion usually reverses the
change and specific treatment is only necessary occasionally. Mild vasoconstriction
has occasionally been observed, particularly in patients recently treated
Symptoms of angina pectoris have been observed in 1 - 3 % of patients,
particularly in the elderly and in patients with severe coronary heart
disease, especially in the absence of pronounced heart failure.
In rare cases serious cardiovascular adverse reactions including myocardial
ischemia, myocardial infarction, and heart arrest may occur.
The following adverse effects have been reported in 1 - 3 % of patients:
headache, nausea, chest pain, palpitations, shortness of breath, frequency
and urgency of micturition, vomiting. Signs and symptoms of myocardial
ischemia may occur occasionally. Reactions suggestive of hypersensitivity
e.g. skin rash, fever, eosinophilia and bronchospasm, occur rarely.
Phlebitis at the infusion site has been reported occasionally. Local
inflammatory changes have been described following inadvertent extravasation;
skin necrosis has been reported in isolated cases.
Like other catecholamines, dobutamine can produce a mild reduction in
serum potassium concentration, but rarely hypokalaemia.
Dobutamine can inhibit platelet function in vivo and in vitro. Inhibition
of platelet aggregation is transient and clinically relevant only with
continuous infusion for days. Petechial bleeding has been observed in
In children, the increase in heart rate and/or blood pressure may be
more pronounced and the fall in pulmonary capillary pressure less than
in adults. Rises in the pulmonary capillary pressure have also been
observed, particularly in children under 1 year of age.
Symptoms of overdosage:
Overdoses of dobutamine have been reported rarely. The symptoms, generally
due to excessive ß-receptor stimulation, may include nausea, vomiting,
loss of appetite, tremor, anxiety, palpitations, headache, angina pectoris
and non-specific chest pain. The positive inotropic and chronotropic
cardiac action can lead to hypertension, myocardial ischaemia, tachyarrhythmias
(supraventricular or ventricular), and ventricular fibrillation. Hypotension
may result from peripheral vasodilatation.
Therapy of overdosage:
Temporarily discontinue the dobutamine infusion, since the duration
of action of dobutamine is short (half-life 2 - 3 minutes). Monitor
the patient and, if necessary, initiate resuscitative measures immediately.
Maintain vital signs, blood gases and serum electrolytes within acceptable
limits. Severe ventricular arrhythmias may be treated with lidocaine
or a ß-blocker (e.g. propranolol). Hypertension usually responds
to a reduction in dose or discontinuation of therapy.
If the product is inadvertently ingested, unpredictable absorption
may occur from the mouth or gastrointestinal tract. The administration
of activated charcoal may possibly reduce absorption and is frequently
more effective than the administration of emetics or gastric lavage.
Forced diuresis, peritoneal dialysis, haemodialysis or charcoal haemoperfusion
have not been established as beneficial in dobutamine overdose.
5. Pharmacological Properties
Dobutamine is a direct-acting inotropic agent of which the
primary activity results from stimulation of cardiac ß ¹
- as well as a ¹ -receptors. It is also indirectly-acting chronotrope,
through peripheral vasodilatation.
increases myocardial contractility with a rise in stroke
volume and cardiac output,
exhibits agonistic action on peripheral ß ²
-receptors and to a lesser extent on a ² -receptors, so may produce
positive chronotropic effects on peripheral vessels but these are less
pronounced than with some other catecholamines,
produces dose-dependent haemodynamic effects: increased
cardiac output, mainly as a result of the rise in stroke volume; increased
heart rate, particularly at higher doses; decreases in left ventricular
filling pressure, in systemic vascular resistance and, at high doses,
in pulmonary vascular resistance,
decreases sinus node recovery time and AV conduction time,
reduces platelet aggregation transiently,
increases myocardial oxygen requirements, but the increase
in cardiac output and the resulting increase in coronary blood flow
usually compensate these effects and tend to lead to a rather more favourable
oxygen balance than with other positive inotropic substances,
does not affect dopamine receptors and (unlike dopamine,
for example) does not affect the release of endogenous noradrenaline,
has no direct dopaminergic effect on renal perfusion,
can lead to a tendency to arrhythmias.
In heart failure and concurrent acute or chronic myocardial
ischemia, dobutamine should be administered at dosages that do not cause
marked increases in heart rate and/or blood pressure, as otherwise (especially
in relatively good ventricular function) an increase in ischaemia cannot
Pharmacological tolerance may occur after 72 hours
of continuous infusion, probably by a reduced activation capacity of
the adenyl cyclase system.
The action sets in about 1 - 2 minutes after the start of infusion
whereas plasma steady-state levels with continuous infusion are reached
only after 10 to 12 minutes. The steady-state plasma levels increase
linearly as a function of the dosage and rate of infusion. The half-life
is 2 - 3 minutes. The volume of distribution is 0.2 l/kg body weight.
The plasma clearance is independent of the cardiac
output and is 2.4 l/min/m 2 . Dobutamine is metabolised predominantly
in the tissues and in the liver. Metabolisation is mainly to conjugated
glucuronides and to pharmacologically inactive 3-O-methyldobutamine.
Excretion is via the kidneys and bile. Over two-thirds of the dose is
eliminated with the urine as glucoronides and 3-O-methyldobutamine.
5.3. Preclinical safety data
The LD 50 after intravenous administration of dobutamine is approximately
100mg/kg in mice and rats and >40mg/kg in dogs. The action sets in
immediately in the form of short lasting collapse. The surviving animals
show hyperactivity with raised heart and respiration rates, mydriasis
and salivation during the first hours.
Repeated dose toxicity:
In subchronic toxicity testing (over 14 days), the doses tolerated were
10mg/kg/day i.v. in the rat and 15mg/kg 4 times daily or 50 m g/kg/min
(as a continuous infusion) in the dog. Cardiotoxic effects in the dog
were associated with prompt ECG changes. Intravenous administration
of dobutamine for 30 days revealed no toxic effects at 2mg/kg in the
rat and at 1.4mg/kg in the dog. At daily doses up to 24mg/kg in dogs
and 80mg/kg in rats, both species showed dosage-dependent myocardial
damage and hypertrophy of the acinar cells of the parotid gland. In
the rat, the highest dosage resulted in 100 % mortality within 19 days.
A 6-month investigation in dogs of intravenous doses up to 6mg/kg revealed
no toxicity other than pharmacological effects (tachycardia with raised
amplitudes, skin flushing, prostration, emesis, tremor and salivation).
No mutagenicity or carcinogenicity tests have been
There was no evidence of teratogenicity in the rat or rabbit. Disturbed
implantation and pre- and post-natal growth retardation of the offspring
of rats were observed at maternally toxic doses. Dobutamine had no effect
on the fertility of male and female rats.
No adverse effects at the injection site were observed after intravenous
injection in rabbits.
6. Pharmaceutical Particulars
6.1 List of excipients
L-cysteine hydrochloride monohydrate
citric acid monohydrate
water for injection
Do not add Dobutamin Admeda to 5% sodium bicarbonate or any
other strongly alkaline solution. Be-cause of potential physical incompatibilities,
it is recommended that Dobutamin Admeda is not mixed with other drugs
in the same solution.
Known physical incompatibilities exist with:
Ethacrylic acid (sodium salt)
Hydrocortisone sodium succinate
Dobutamine can interfere with HPLC assay of chloramphenicol.
6.3. Shelf life
Dobutamin Admeda 250 has a shelf life of three years.
6.4. Special precautions for storage
Do not store above 30°C. The in-use shelf-life is limited
to 24 hours at 2-8 °C (according to the Note for guidance on maximum
shelf life for sterile products for human use after first opening or
following reconstitution (CPMP/QWP/159/96)).
Since Dobutamin Admeda is not intended for multiple dosing from the
same containers, it contains no preservatives. The temperature stability
information given in the table below for Dobutamin Admeda and Dobutamin
Admeda in solutions relates only to physical-chemical properties and
disregard the microbiological aspect. Dobutamin Admeda should always
be prepared for administration under optimal hygienic (aseptic) conditions.
Physical and chemical storage stability:
|| Dobutamin Admeda 250
| Storage at 60°C
||min. 6 months
|Storage at 40°C
||min. 6 months
|Storage at 30°C
|Storage at 2-8°C with NaCl *
||stable for up to 14 days
|Storage at 2-8°C with glucose *
||stable for up to 14 days
|Storage at 2-8°C with Ringer's lactate *
||stable for up to 14 days
|Storage at RT with NaCl *
|Storage at RT with glucose *
|Storage at RT with Ringer's lactate *
*Mixing ratio: contents of 1 ampoule in 500 ml infusion solution
6.5. Nature and contents of container
Colourless score-ring ampoules hydrolytic resistance glass
type I (Ph.Eur.). Each pack contains 1 (one) ampoule (50 ml) in folding,
hard cardboard box.
6.6. Instructions for use and handling
7. Marketing Authorization Holder
Admeda Arzneimittel GmbH
8. Numbers In The Community Register Of Medicinal Products
9. Date Of First Authorization/Renewal Of Authorization
10. Date Of (Partial) Revision Of The Text