Dobutamine 12.5 mg/ml, Concentrate for solution for infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Dobutamine 12.5 mg/ml, Concentrate for solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each ml contains dobutamine 12.5 mg (as 14.01 mg dobutamine hydrochloride). Each 20 ml vial contains 250 mg of dobutamine (as 280.2 mg dobutamine hydrochloride).

Excipient(s) with known effect:

Sodium metabisulfite (E223) – 0.24 mg/ml

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Concentrate for solution for infusion.

Clear, colourless to pale straw-coloured solution.

pH ranges between 2.5 and 5.5.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Dobutamine is indicated in adults who require inotropic support in the treatment of low output cardiac failure normally associated with myocardial infarction, open heart surgery, cardiomyopathies, septic shock and cardiogenic shock.

Dobutamine may also be used for cardiac stress testing as an alternative to exercise in patients for whom routine exercise cannot be satisfactorily performed.

Paediatric population

Dobutamine is indicated in all paediatric age groups (from neonates to 18 years of age) as inotropic support in low cardiac output hypoperfusion states resulting from decompensated heart failure, following cardiac surgery, cardiomyopathies and in cardiogenic or septic shock.

4.2 Posology and method of administration

For intravenous use only.

Posology

Adult

Inotropic support of the myocardium:

The usual dose is 2.5 to 10 micrograms/kg/minute, which should be adjusted according to the patient’s heart rate, blood pressure, cardiac output and urine output. The infusion must be started at a rate of 2.5 micrograms/kg/min and the dose may be increased in intervals of 10-30 minutes until desired hemodynamic response is achieved or until side effects, such as excessive tachycardia, arrhythmia, headache or tremor limit a further increase in dosage. The dose should be adjusted individually according to heart rate and rhythm, blood pressure and urinary flow. Occasionally, a dose as low as 0.5 micrograms/kg/minute will produce a response. Up to 40 micrograms/kg/minute may be required.

During prolonged continuous infusion (48-72 hours), a decrease in haemodynamic response may occur, which makes an increase in dose necessary.

Dosage for cardiac stress testing:

The use of dobutamine in cardiac stress testing should only be undertaken in units which already perform exercise stress testing and all normal care and precautions required for such testing are also required when using dobutamine for this purpose including the availability of a defibrillator and personnel specially trained in resuscitation are present.

The recommended dosage is an incremental increase in infusion rates from 5 micrograms/kg/minute to 10, 20, 30 and a maximum of 40 micrograms/kg/minute, each dose being infused for 3 minutes. In addition, atropine can be added during further infusion of the peak dose. Continuous electrocardiogram (ECG) monitoring is required and the infusion may be terminated in the event of ST-segment depression of > 0.2 mV (2 mm) measured 80 ms after the J point, a ST-segment elevate of > 0.1 mV (1 mm) in patients without history of myocardial infarction, or any significant cardiac arrhythmias.

The infusion of dobutamine should be terminated if the heart rate reaches 85% of the age-predicted maximum, systolic blood pressure rises above 220 mmHg or a symptomatic decrease in systolic blood pressure > 40 mmHg from baseline, new cardiac wall motion abnormalities, severe chest pain or any non-tolerable adverse effect occurs.

Elderly:

No variation in dosage is suggested. Close monitoring is required for blood pressure, urine flow and peripheral tissue perfusion.

Cardiac stress testing: when used as an alternative to exercise for cardiac stress testing the recommended dose should start at 5 micrograms/kg/minute, and the dose should be increased incrementally by 5 micrograms/kg/minute every 8 minutes to a maximum rate of 20 micrograms/kg/minute. Continuous ECG monitoring is essential and the infusion terminated in the event of > 3 mm ST segment depression or any ventricular arrhythmia. The infusion should also be terminated if heart rate reaches the age/sex maximum, systolic blood pressure rises above 220 mm Hg or any side effects occur.

Paediatric population

For all paediatric age groups (neonates to 18 years) an initial dose of 5 micrograms/kg/minute, adjusted according to clinical response to 2 – 20 micrograms/kg/minute is recommended. Occasionally, a dose as low as 0.5-1.0 micrograms/kg/minute will produce a response.

There is reason to believe that the minimum effective dosage for children is higher than for adults. Caution should be taken in applying high doses, because there is also reason to believe that the maximum tolerated dosage for children is lower than the one for adults. Most adverse reactions (tachycardia in particular) are observed when dosage was higher than/equal to 7.5 micrograms/kg/minute, but reducing or termination of the rate of dobutamine infusion is all that is required for rapid reversal of undesirable effects.

A great variability has been noted between paediatric patients in regard to both the plasma concentration necessary to initiate a hemodynamic response (threshold) and the rate of hemodynamic response to increasing plasma concentrations, which demonstrates that the required dose for children cannot be determined a priori and should be titrated in order to allow for the supposedly smaller “therapeutic width” in children.

Method of administration

Dobutamine should be diluted before use and administered by IV infusion only.

The concentration of the dobutamine administered depends upon the dosage and fluid requirements of the individual patient. The final concentrations generally used for perfusion are 250 micrograms/ml, 500 micrograms/ml or 1000 micrograms/ml. For special precautions for storage of the prepared diluted infusion see section 6.4. High concentrations of dobutamine should only be given with an infusion pump or other suitable apparatus to ensure accurate dosage. Due to its short half-life dobutamine should be administered as a continuous intravenous infusion. Dobutamine should be administered intravenously through an intravenous needle or catheter. The following sterile solutions for IV infusion may be used for the dilution of dobutamine before use: 5% Dextrose Injection, 5% Dextrose and 0.45% Sodium Chloride Injection, 5% Dextrose and 0.9% Sodium Chloride Injection, 10% Dextrose Injection, multi-electrolyte with 5% Dextrose Injection, Lactated Ringer's Injection, 5% Dextrose in Lactated Ringer's Injection, 20% Mannitol in Water for Injection, 0.9% Sodium Chloride Injection and Sodium Lactate Injection.

Dosage for Infusion delivery systems:

One vial Dobutamine 12.5 mg/ml (250 mg/20 ml) diluted to a solution volume of 500 ml (final concentration 0.5 mg/ml) with any of the approved diluents (see section 6.6).

* For double concentration, i.e. 500 mg Dobutamine added to 500 ml, or 250 mg added to 250 ml solution, infusion rates must be halved.

The dose to be administered can be calculated taking into account the table below. Infusion rates in millilitres/min can be obtained by multiplying infusion rates for each concentration (ml/kg/min) by patient’s weight (kg).

Dosage for syringe pumps:

One vial Dobutamine 12.5 mg/ml (250 mg/20 ml) diluted to a solution volume of 50 ml (final concentration 5 mg/ml) with any of the approved diluents (see section 6.6).

Paediatric population

For continuous intravenous infusion using an infusion pump, dilute to a concentration of 0.5 to 1 mg/mL (max 5 mg/mL if fluid restricted) with Glucose 5% or Sodium Chloride 0.9%. Infuse higher concentration solutions through central venous catheter only. Dobutamine intravenous infusion is incompatible with bicarbonate and other strong alkaline solutions.

Neonatal intensive care

Dilute 30 mg/kg body weight to a final volume of 50 mL of infusion fluid. An intravenous infusion rate of 0.5 mL/hour provides a dose of 5 micrograms/kg/minute.

For instructions on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

Dobutamine is contraindicated in the following situations:

• Hypersensitivity to the active substance, to any of the excipients listed in section

  6.1 or to sodium metabisulfite or other sulfates.

• known mechanical obstruction of ventricular filling and/or ventricular ejection such as cardiac tamponade, severe aortic valve stenosis, constrictive pericarditis, hypertrophic obstructive cardiomyopathy or idiopathic hypertrophic subaortic stenosis.
• Hypovolaemic conditions, unless corrected by blood volume expansion.
• Untreated severe ventricular arrhythmia.
• In addition to an exercise tolerance test: Recent myocardial infarction (in the past 30 days), aortic dissection, aortic aneurysm, unstable angina pectoris, untreated hypertension, untreated arrhythmia (including untreated atrial fibrillation), known severe ventricular arrhythmia, electrolyte disturbances and severe anaemia.
• Phaeochromocytoma.

4.4 Special warnings and precautions for use

In the event of an unwanted increase in heart rate or systolic blood pressure or if arrhythmia occurs, the dose of dobutamine should be reduced or the administration drug should be discontinued temporarily.

Dobutamine may accelerate or exacerbate ventricular ectopic activity; in rare cases cause tachycardia or ventricular fibrillation. Dobutamine increases atroventricular conduction, and patients with atrial flutter or fibrillation often develop a rapid ventricular response.

Dobutamine may potentially produce a significant acceleration in heart rate or an excessive increase in blood pressure, which may accelerate onset of myocardial ischemia, and cause chest pain and ST segment elevation. Vigilance is therefore required for any signs of onset of myocardial infarction resulting from these effects.

Dobutamine does not improve haemodynamic in most patients with mechanical obstruction affecting ventricular filling and/or ejection, (see section 4.3).

Insufficient inotropic response may be observed in patients with markedly reduced ventricular function, for example in the event of , e.g. cardiac tamponade, aortic valve stenosis and idiopathic hypertrophic subaortic stenosis (see section 4.3).

Via competitive receptor inhibition, the catecholaminergic effect of dobutamine can be reduced by simultaneous administration of a beta blocking agent. In addition, the dominant alpha- adrenergic effects at that time may cause peripheral vasoconstriction, causing an increase in blood pressure.

Administration

Before administration of dobutamine, hypovolaemia must be corrected with an appropriate plasma substitute (plasma expander solution, see section 4.3) in order to increase plasma volume.

As with other medicinal products endowed with beta-2-agonist activity, dobutamine may also slightly reduce serum potassium concentrations and, relatively infrequently, cause hypokalaemia. Monitoring of serum potassium levels is therefore recommended during treatment with dobutamine.

Heart rate, cardiac rhythm, blood pressure, and infusion rate should be carefully monitored during treatment with dobutamine. When initiating treatment with dobutamine, electrocardiographic monitoring is recommended until a stable response is achieved.

Warnings

Dobutamine is to be used with particular caution in the event of severe hypotension with cardiogenic shock (blood pressure less than 70 mm Hg). If there is a rapid fall in blood pressure, reducing the dose or stopping the infusion allows base-line blood pressure values to be restored. In only one case, a patient required intervention, and correction was not immediately obtained.

If blood pressure remains low, or if it decreases gradually during dobutamine administration despite normal ventricular pressure and cardiac output, the use of a peripheral vasoconstrictor, such as norepinephrine or dopamine, may be recommended.

Dobutamine concentrate for solution for infusion contains sodium metabisulfite in the formulation, which may rarely cause type severe hypersensitivity reactions and bronchospasm, including anaphylaxis and asthma attacks, possibly life-threatening or of a less severe nature, particularly in hypersensitive patients.

The prevalence of hypersensitivity to sulfite in the general population is unknown, but probably low. However, this type of hypersensitivity appears to be more common in asthmatic patients (see section 4.3).

Dobutamine may only be used under the direct supervision of specialists equipped with intensive monitoring devices of cardiovascular and renal parameters, particularly, blood volume, myocardial contractility, electrocardiography, urine production, blood pressure and pulse and, if possible cardiac output and pulmonary wedge pressure (PAWP).

After discontinuation of prolonged treatment (more than 7 days) with dobutamine, a reduction in cardiac output and an increase in PAWP was observed.

An increase in blood pressure may occur in patients with pre-existing hypertonia. As the effect of dobutamine is unknown in patients with impaired renal and hepatic function, close observation of the patient is recommended.

Continuous intravenous infusion of dobutamine is only relatively effective, of limited benefit and may in fact even be harmful in patients with advanced heart failure, both in terms of quality of life and the odds of survival.

Dobutamine may modify plasma insulin and glucose levels. In diabetic patients, blood glucose should therefore be monitored and insulin dose adjusted if necessary.

The use of dobutamine as an alternative to exercise tolerance tests is not recommended in patients with unstable angina pectoris, bundle branch block or heart disease making them unfit for exercise tolerance tests.

Like other catecholamines, dobutamine may cause angina pectoris to develop in patients with ischaemic heart disease. Patients with ischaemic cardiac abnormalities will therefore be closely monitored if treated with dobutamine.

Particular caution should be exercised when dobutamine is administered to patients treated with monoamine oxidase inhibitors (MAOIs) or patients with pheochromocytoma or hyperthyroidism. In these patients, elevated catecholamine levels or hypersensitivity may cause a significant increase in blood pressure and, heart rate, together with and increased risk of arrhythmia.

Myocardial rupture is a potential complication of myocardial infarction. The risk of myocardial rupture (septal free wall and septum) may be influenced by numerous factors, including the previous infarct, and time of occurrence. Very rare cases of fatal acute myocardial rupture have been reported during dobutamine stress testing. These had been performed on patients prior to discharge from hospital after a recent myocardial infarction (in the past 4-12 days).

In the reported cases of free wall rupture, the echocardiogram showed a thinned dyskinetic lower wall. Dobutamine stress tests expose patients to a risk of myocardial rupture; this risk must be discussed in detail with the patient before performing the test.

Dobutamine stress echocardiography

In view of the potentially fatal complications only specialists with sufficient experience in stress echocardiography should undertake this type of test in the context of ischaemia and diagnosis.

Dobutamine stress echocardiography in the context of ischemia and diagnosis must be discontinued if one of the following diagnostic criteria are observed:

• maximal heart rate [(220-age in years) x 0.85];
• systolic blood pressure decrease > 20 mmHg;
• blood pressure increase to > 220/120 mmHg;
• progressive symptoms (angina pectoris, dyspnoea, dizziness, ataxia);
• progressive arrhythmia (e.g. coupling, ventricular fibrillation);
• progressive conduction disturbances;
• recent-onset heart wall motility disorders in > 1 wall segment (16-segment model);
• increase of end systolic volume;
• development of repolarisation abnormality (due to horizontal ischemia reduction in ST segment depression > 0.2 mV over an interval of 80 (60) ms after the J point relative to the reference value , progressive or monophasic ST segment elevation > 0.1 mV in patients with a history of myocardial infarction;
• maximum dose reached.

Stress cardiomyopathy (Takotsubo syndrome) is a possible severe complication of the use of dobutamine during stress echocardiography (see section 4.8). The administration of dobutamine for stress echocardiography should only be undertaken by a physician experienced with the procedure. The physician should be vigilant during the test and the recovery period and be prepared for appropriate therapeutic intervention during the test. In the event of stress cardiomyopathy (Takotsubo syndrome), dobutamine should be stopped immediately.

In the event of severe complications (see section 4.8) dobutamine stress echocardiography must be stopped immediately.

After termination of infusion, patients must be monitored until stabilised. This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially ‘sodium-free’.

Paediatric population

Dobutamine has been administered to children in a state of low cardiac output associated hypo-perfusion resulting from decompensated heart failure, after heart surgery, and in the event of cardiogenic or septic shock.

Some of the haemodynamic effects of dobutamine hydrochloride may be quantitatively or qualitatively different in children as compared to adults.

Increases in heart rate and blood pressure appear to be more frequent and intense in children. Pulmonary arterial wedge pressure may not decrease in children, like it does in adults. In contrast, it may increase, especially in infants less than one year old. The neonate cardiovascular system has been reported to be less sensitive to dobutamine, and hypotensive effect seems to be observed more often in adult patients than in young children.

For these reasons, administration of dobutamine in children must be closely monitored, taking into consideration these pharmacodynamics data specific to the paediatric population.

4.5 Interaction with other medicinal products and other forms of interaction

Beta-blocking agents

In animals the cardiac effects of dobutamine are countered by beta blocking agents such as propranolol and metoprolol, which is evidenced by the predominance of alpha- blocking substances and increased peripheral resistance.

Conversely, the alpha-blocking effect gives rise to the onset of beta-1- and beta-2- adrenergic effects, inducing tachycardia and vasodilatation.

Adding dipyridamole to dobutamine during echocardiography may cause potentially dangerous hypotension. The combination must not be used in patients thought to present cardiac abnormalities affecting the coronary artery.

Dobutamine stress echocardiography

In the event of anti-anginal therapy namely with medicinal products that slow the heart rate, such as beta-blocking agents, the ischemic reaction to stress will be less pronounced or even non-existent.

Antianginal therapy must therefore be discontinued for 12 hours prior to dobutamine stress echocardiography.

When atropine is administered with a maximum dose of dobutamine, the following is observed:

• Following extended stress echocardiography, at a higher total dose of dobutamine and the concomitant administration of atropine, there is an increased risk of adverse reactions.

General anaesthetics

Ventricular arrhythmia has been reported in animals having received usual doses of dobutamine with halothane or cyclopropane anaesthesia. Caution should therefore be exercised when administering dobutamine to patients receiving these anaesthetics.

Simultaneous use of dobutamine and MAOIs may cause a marked increase in blood pressure and heart rate together with a higher incidence of arrhythmias. This combination may also give rise to potentially fatal situations such as hypertensive crisis, circulatory collapse, intracranial haemorrhage and arrythmia.

The use of premedication or concomitant administration of ß- blocking agents may cause a reduction in inotropic and chronotropic effects as a result of competitive binding to the beta- adrenergic receptors and lead to domination of the alpha-adrenergic effects, shown by peripheral vasodilatation.

When used in combination with dobutamine, peripheral vasodilators (e.g. nitrates, sodium nitroprusside) may cause an increase in cardiac output and a decrease in systemic peripheral resistance and ventricular filling pressure more than any other medicinal product.

In a clinical study, co-administration of theophylline caused an increase in the heart rate.

Co-administration dobutamine and dopamine caused a marked increase in systemic blood pressure and prevents an increase in ventricular filling pressure, as shown with administration of dopamine only.

Concomitant administration of dobutamine and peripheral vasoconstrictors, such as norepinephrine produces a stronger increase in systemic blood pressure than individual use of these medicinal products as monotherapy.

Concomitant administration of dobutamine and ACE-inhibitors (e.g. captopril) may cause an increase in cardiac output associated by increased myocardial oxygen consumption. Chest pain and arrhythmia have been reported with this combination.

The effects of dobutamine may be potentiated by the simultaneous use with entacapone. Antipsychotic agents potentially thwart the hypertensive effects of dobutamine.

Co-administration of dobutamine and doxapram causes an increased risk of hypertension

Co-administration of dobutamine with ergotamine and methysergide is also associated with an increased risk of ergot poisoning.

Concomitant use of dobutamine and oxytocin may induce hypertension (due to the increased vasopressor effects).

Addition of atropine sulfate reinforces the increase in heart rate induced by dobutamine and may thwart the reduction in heart rate, as shown in dobutamine stress echocardiography.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no unequivocal data on the safety of dobutamine in pregnant women. Animal studies do not indicate direct or indirect harmful effects with respect to gestation, embryofoetal development, birth and post-natal development, but it is not known whether dobutamine crosses the placental barrier. The potential risk for humans is not known. Dobutamine must not be used during pregnancy, unless the potential benefits to the mother outweigh any risks to the unborn child.

Breast-feeding

It is unknown whether dobutamine is excreted in animal or human breast milk. A decision must be made whether to discontinue breast-feeding or to discontinue therapy with dobutamine taking into account the benefit of breast-feeding to the child and the benefit of dobutamine therapy to the woman.

4.7 Effects on ability to drive and use machines

Not relevant given the therapeutic indications and short half-life of dobutamine. There are no data evidencing any effect of dobutamine on the ability to drive or use machines.

4.8 Undesirable effects

Infusions for up to 72 hours were not associated with a higher number of undesirable effects than infusions over a shorter period. Continuous dobutamine infusions for more than 72 hours have been shown to cause the development of partial tolerance. In this case, administration of higher doses may prove necessary in order to achieve the same result.

The following terminology is used to classify undesirable effects:

≥

Within each frequency grouping, undesirable effects are presented in decreasing order of seriousness.

Blood and lymphatic system disorders

Not known: thrombocytopenia

Immune system disorders

Common: Hypersensitivity reactions including rash, fever, eosinophilia, bronchospasm and eosinophilic myocarditis have been reported. Uncommon: Sodium metabisulfite may cause allergic reactions, including anaphylaxis and asthma attacks, of a life-threatening or less severe nature (see section 4.4).

Metabolism and nutrition disorders

Very rare: Like other catecholamines, a decrease in serum potassium levels may occur. Monitoring of serum potassium levels must be envisaged.

Nervous system disorders

Common: headache

Very rare: Myoclonus has been reported in patients with severe renal impairment treated with dobutamine.

Cardiac disorders

Very common: heart rate acceleration, palpitations, intense chest pain, irregular heart rate, arrhythmia, ventricular tachycardia, coronary artery spasm, ST-segment elevation on ECG

Uncommon: atrial fibrillation, ventricular fibrillation, obstructed left ventricular ejection

Very rare: myocardial ischaemia, myocardial infarction, eosinophilic myocarditis, fatal myocardial rupture during dobutamine stress tests (see section 4.4) Not known: stress cardiomyopathy (Takotsubo syndrome) (see section 4.4)

Vascular disorders

Common: Hypertension. A marked increase in systolic blood pressure is an indication of overdose (see section 4.5).

Uncommon: Hypotension (see sections 4.4 and 4.5). Mild vasoconstriction, particularly in patients who have previously been treated with beta-blocking agents.

Respiratory, thoracic and mediastinal disorders

Common: shortness of breath, bronchospasm, asthma (see Immune system disorders)

Gastrointestinal disorders

Common: nausea

Renal and urinary disorders

Not known: increased micturition urgency

General disorders and administration site conditions

Common: non-specific chest pain

Rare: Cases of phlebitis have been occasionally reported, and local inflammation has been reported after accidental infiltration.

Very rare: cutaneous necrosis

Paediatric population

Undesirable effects include elevation of systolic blood pressure, systemic hypertension or hypotension, tachycardia, headache, and elevation of pulmonary arterial wedge pressure leading to congestion and pulmonary oedema, and symptomatic complaints.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme, at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Rare cases of overdose have been reported.

Symptoms

Symptoms of toxicity include: anorexia, nausea, vomiting, tremor, anxiety, palpitations, headache, dyspnoea, fatigue, anginal pain and non-specific chest pain. The positive inotropic and chronotropic effects of dobutamine may cause hypertension, tachyarrhythmia, myocardial ischemia and ventricular fibrillation. Hypotension may occur due to peripheral vasodilatation. Dobutamine generally has a relatively short duration of action (half-life: approximately 2 minutes).

Treatment of overdose

Due to the short half-life of dobutamine, a reduction in infusion rate or a temporary discontinuation of the infusion is generally necessary, until stabilization of the patient. The patient should be closely monitored and resuscitation measures must be taken immediately, if necessary.

The benefit of forced diuresis, peritoneal dialysis, haemodialysis or haemoperfusion with activated charcoal has not been demonstrated in the treatment of dobutamine overdose.

With oral administration, the quantity absorbed from the mouth or gastrointestinal tract cannot be predicted.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: 3.3 Sympathomimetic, ATC code: C01CA07 dobutamine.

Mechanism of action

Dobutamine is a selective beta-adrenergic agonist whose mechanism of action is complex.

It is believed that the β

-adrenergic effects result from stimulation of adenyl cyclase activity. In therapeutic doses, dobutamine also has mild β

₂ - and α

₁ - adrenergic receptor agonist effects, which are relatively balanced and result in minimal net direct effect on systemic vasculature. Dobutamine does not cause release of endogenous norepinephrine. The main effect of therapeutic doses of dobutamine is cardiac stimulation.

While the positive inotropic effect of the drug on the myocardium appears to be mediated principally via β

₁-adrenergic stimulation, experimental evidence suggests that α

₁-adrenergic stimulation may also be involved and that the α

₁-adrenergic activity results mainly from the (-)-stereoisomer of the drug.

The β

₁-adrenergic effects of dobutamine exert a positive inotropic effect on the myocardium and result in an increase in cardiac output due to increased myocardial contractility and stroke volume. Increased left ventricular filling pressure decreases in patients with congestive heart failure. In therapeutic doses, dobutamine causes a decrease in peripheral resistance; however, systolic blood pressure and pulse pressure may remain unchanged or be increased because of augmented cardiac output. With usual doses, heart rate is usually not substantially changed. Coronary blood flow and myocardial oxygen consumption are usually increased because of increased myocardial contractility.

Dobutamine facilitates atrio-ventricular conduction and shortens or causes no important change in intra-ventricular conduction. The tendency of dobutamine to induce cardiac arrhythmias may be slightly less than that of dopamine and is considerably less than that of isoproterenol or other catecholamines. Pulmonary vascular resistance may decrease if it is elevated initially and mean pulmonary artery pressure may decrease or remain unchanged. Dobutamine does not seem to affect dopaminergic receptors and causes no renal or mesenteric vasodilatation; however, urine flow may increase because of increased cardiac output.

Paediatric population

Dobutamine 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 the heart rate and arterial blood pressure to increase more in children than in adults. Pulmonary wedge pressure may increase during infusion of dobutamine in children 12 months of age or younger.

Increases in cardiac output seems to begin at IV infusion rates as low as 1.0 micrograms/kg/minute, increases in systolic blood pressure at 2.5 micrograms/kg/minute, and heart rate changes at 5.5 micrograms/kg/minute.

The increase of dobutamine infusion rates from 10 to 20 micrograms/kg/minute usually results in further increases in cardiac output.

5.2 Pharmacokinetic properties

Absorption: Orally administered dobutamine is rapidly metabolised in the GI tract. Following IV administration, the onset of action of dobutamine occurs within 2 minutes. Peak plasma concentrations of the drug and peak effects occur within 10 minutes after initiation of an IV infusion. The effects of the drug cease shortly after discontinuing an infusion.

Distribution: It is not known if dobutamine crosses the placenta or is distributed into milk.

Elimination: The plasma half-life of dobutamine is about 2 minutes. Dobutamine is metabolised in the liver and other tissues by catechol-o-methyltransferase to an inactive compound, 3-O-methydobutamine and by conjugation with glucuronic acid. Conjugates of dobutamine and 3-O-methyldobutamine are excreted mainly in urine and to a minor extent in faeces.

Paediatric population

In most paediatric patients, there is a log-linear relationship between plasma dobutamine concentration and hemodynamic response that is consistent with a threshold model.

Dobutamine clearance is consistent with first-order kinetics over the dosage range of 0.5 to 20 micrograms/kg/minute. Plasma dobutamine concentration can vary as much as two-fold between paediatric patients at the same infusion rate and there is a wide variability in both the plasma dobutamine concentration necessary to initiate a hemodynamic response and the rate of hemodynamic response to increasing plasma concentrations. Therefore, in clinical situations dobutamine infusion rates must be individually titrated.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans based on conventional studies of repeated dose toxicity. Studies on the mutagenic or carcinogenic potential of dobutamine have not been conducted. Studies in rats and rabbits revealed no evidence of fetal harm or teratogenic effect. No influence on fertility was seen in rats.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Sodium Metabisulfite (E223)

Sodium Hydroxide

Hydrochloric Acid

Water for Injections

6.2 Incompatibilities

Do not add Dobutamine to 5% Sodium Bicarbonate intravenous infusion or to any other strongly alkaline solutions. Because of potential physical incompatibilities, it is recommended that dobutamine hydrochloride not be mixed with other drugs in the same solution.

Dobutamine injections should not be used with other agents or diluents containing both sodium metabisulfite and ethanol.

6.3 Shelf life

2 years

Chemical and physical in-use stability has been demonstrated for 24 hours at 25ºC (room temperature).

From a microbiological point of view, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user and would normally not be longer than 24 hours at 2 to 8ºC, unless dilution has taken place in controlled and validated aseptic conditions.

6.4 Special precautions for storage

Do not store above 25°C.

For storage conditions after dilution of the medicinal product, see section 6.3.

6.5 Nature and contents of container

Dobutamine is packed in 20 ml clear glass vials with bromobutyl rubber stoppers, sealed with aluminium flip-off cap.

Packs of 10 vials.

6.6 Special precautions for disposal

The content of 20 ml vial of Dobutamine must be diluted to at least 50 ml, prior to administration in an IV container with one of the intravenous solutions listed below:

• 5% Dextrose Injection,
• 5% Dextrose and 0.45% Sodium Chloride Injection,
• 5% Dextrose and 0.9% Sodium Chloride Injection,
• 10% Dextrose Injection,
• multi-electrolyte with 5% Dextrose Injection;
• Lactated Ringer's Injection;
• 5% Dextrose in Lactated Ringer's Injection;
• 20% Mannitol in Water for Injection;
• 0.9% Sodium Chloride Injection,
• Sodium Lactate Injection.

For example, diluting to 250 ml or 500 ml will provide the following concentrations for administration:

250 ml contains 1,000 micrograms/ml of dobutamine

500 ml contains 500 micrograms/ml of dobutamine

The prepared solution should be used within 24 hours.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Hikma Farmacêutica (Portugal), S.A.

Estrada do Rio da Mó, nº8, 8A, 8B

Fervença

2705-906 Terrugem SNT

Portugal

8 MARKETING AUTHORISATION NUMBER(S)

PL 15413/0100

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

26/02/2021

10 DATE OF REVISION OF THE TEXT

11/12/2025