4.1. Therapeutic indications

Adults

Dobutamine is indicated for patients who require a positive inotropic support in the treatment of cardiac decompensation due to depressed contractility.

In cardiogenic shock characterised by heart failure with severe hypotension and in case of septic shock Dobutamine may be useful if added to dopamine in case of disturbed ventricular function, raised filling pressure of the ventricles and raised systemic resistance.

Dobutamine may also be used for detection of myocardial ischaemia and of viable myocardium within the scope of an echocardiographic examination (dobutamine stress echocardiography), if patients cannot undergo a period of exercise or if the exercise yields no information of value.

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

Posology

Dobutamine doses must be individually adjusted.

The required rate of infusion depends on the patient's response to therapy and the adverse reactions experienced.

Dosage in adults:

According to experience, the majority of patients respond to doses of 2.5-10 µg dobutamine/kg/min. In individual cases, doses up to 40 µg dobutamine/kg/min have been administered.

Dosage in paediatric patients:

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.

Tables, showing infusion rates with different initial concentrations for various dosages:

Dosage for infusion delivery systems

One ampoule Dobutamine 12.5 mg/ml (250 mg in 20 ml) diluted to a solution volume of 500 ml (final concentration 0.5 mg/ml)

Dosage range

Specifications in ml/h*

(drops/min)

Patient's weight

50 kg

70 kg

90 kg

Low

2.5 µg/kg/min

ml/h

(drops/min)

15

(5)

21

(7)

27

(9)

Medium

5 µg/kg/min

ml/h

(drops/min)

30

(10)

42

(14)

54

(18)

High

10 µg/kg/min

ml/h

(drops/min)

60

(20)

84

(28)

108

(36)

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

Dosage for syringe pumps

One ampoule Dobutamine 12.5 mg/ml (250 mg in 20 ml) diluted to a solution volume of 50 ml (final concentration 5 mg/ml)

Dosage range

Specifications in ml/h

(ml/min)

Patient's weight

50 kg

70 kg

90 kg

Low

2.5 µg/kg/min

ml/h

(ml/min)

1.5

(0.025)

2.1

(0.035)

2.7

(0.045)

Medium

5 µg/kg/min

ml/h

(ml/min)

3.0

(0.05)

4.2

(0.07)

5.4

(0.09)

High

10 µg/kg/min

ml/h

(ml/min)

6.0

(0.10)

8.4

(0.14)

10.8

(0.18)

The chosen syringe pump must be suitable for the volume and rate of administration.

For detailed information about suitable solutions for dilution please see section 6.6.

Dobutamine stress echocardiography (Adult population only)

Administration in stress echocardiography is undertaken by gradually increasing dobutamine infusion.

The most frequently applied dosage scheme starts with 5 µg/kg/min Dobutamine increased every 3 minutes to 10, 20, 30, 40 µg/kg/min until a diagnostic endpoint (see method and duration of application) is reached.

If no endpoint is reached atropine sulfate may be administered at 0.5 to 2 mg in divided doses of 0.25-0.5 mg at 1 minute intervals to increase the heart rate. Alternatively the infusion rate of dobutamine may be increased to 50 µg/kg/min.

The experience in children and adolescents is limited to the treatment of patients requiring positive inotropic support.

Method of administration

Dobutamine 12.5 mg/ml (250 mg in 20 ml)

The infusion solution concentrate must be diluted before administration. Only for intravenous infusion.

Intravenous infusion of dobutamine is possible after dilution with compatible infusion solutions such as: 5% glucose solution, 0.9% sodium chloride or 0.45% sodium chloride in 5% glucose solution. (For detailed information for dilution please see section 6.6.) Infusion solutions should be prepared immediately before use. (For information on shelf life, see section 6.3.)

Due to its short half-life, dobutamine must be administered as a continuous intravenous infusion.

The dose of dobutamine should be gradually reduced when discontinuing therapy.

The duration of treatment depends on the clinical requirements and is to be determined by the physician and should be as short as possible.

If dobutamine is administered continuously for more than 72 hours, tolerance may occur, requiring an increase in the dose.

During the course of dobutamine administration, heart rate, heart rhythm, blood pressure, diuresis and infusion rate should be closely monitored. Cardiac output, central venous pressure (CVP) and pulmonary capillary pressure (PCP) should be monitored if possible.

Paediatric patients: For continuous intravenous infusion using an infusion pump, dilute to a concentration of 0.5 to 1 mg/mL (max 5mg/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.

Dobutamine stress echocardiography (Adult population only)

For detection of myocardial ischaemia and of viable myocardium dobutamine may only be administered by a physician with sufficient experience in conducting cardiology stress tests. Continuous monitoring of all wall areas via echocardiography, and ECG as well as control of blood pressure is necessary.

Monitoring devices as well as emergency medicines must be available (e.g. defibrillator, I.V. beta-blockers, nitrates, etc.) and staff trained in the resuscitation procedure must be present.

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

4.3. Contraindications

Dobutamine must not be used in the case of:

- hypersensitivity to the active substance dobutamine or to any of the excipients listed in section 6.1, including in patients with bronchial asthma with hypersensitivity to sulfites,

- mechanical obstruction of ventricular filling and/or of outflow, such as pericardial tamponade, constrictive pericarditis, hypertrophic obstructive cardiomyopathy, severe aortic stenosis,

- hypovolaemic conditions,

- phaeochromocytoma.

Dobutamine stress echocardiography

Dobutamine must not be used for detection of myocardial ischaemia and of viable myocardium in case of:

- recent myocardial infarction (within the last 30 days),

- unstable angina pectoris,

- stenosis of the main left coronary artery,

- haemodynamically significant outflow obstruction of the left ventricle including hypertrophic obstructive cardiomyopathy,

- haemodynamically significant cardiac valvular defect,

- severe heart failure (NYHA III or IV),

- predisposition for or documented medical history of clinically significant or chronic arrhythmia, particularly recurrent persistent ventricular tachycardia,

- significant disturbance in conduction,

- acute pericarditis, myocarditis or endocarditis,

- aortic dissection,

- aortic aneurysm,

- poor sonographic imaging conditions,

- inadequately treated / controlled arterial hypertension,

- obstruction of ventricular filling (constrictive pericarditis, pericardial tamponade),

- hypovolaemia,

- previous experience of hypersensitivity to dobutamine and in patients with bronchial asthma who are hypersensitive to sulfites,

- phaeochromocytoma.

Note:

If administering atropine, the respective contraindications have to be observed.

4.4. Special warnings and precautions for use

A local increase or decrease of coronary blood flow, which may have an impact on the myocardial oxygen demand, has been observed with dobutamine therapy. The clinical characteristics of patients with severe coronary heart disease may deteriorate, in particular if dobutamine therapy is accompanied by a considerable increase in the heart rate and/or blood pressure. Therefore, as with all positive inotropes, the decision to use dobutamine to treat patients with cardiac ischaemia must be made for each case individually.

Due to the risk of arrhythmias and the uncertainty about long term effects on myocardial dysfunction, inotropic agents, such as dobutamine, should be used with caution in the treatment of Acute Heart Failure (AHF).

As alterations in serum potassium level may occur, the potassium level should be monitored.

If dobutamine is administered continuously for more than 72 hours, tolerance phenomena (tachyphylaxis) may occur, requiring dosage increase.

Precipitous decreases in blood pressure (hypotension) 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, but rarely intervention may be required and reversibility may not be immediate.

Hypovolaemia should be corrected before administering dobutamine.

Dobutamine may interfere with HPLC determination of chloramphenicol.

Paediatric population

Dobutamine has been administered to children with low-output hypoperfusion states resulting from decompensated heart failure, cardiac surgery, and cardiogenic and septic shock. Some of the haemodynamic effects of dobutamine hydrochloride may be quantitatively or qualitatively different in children as compared to adults.

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. The neonate cardiovascular system has been reported to be less sensitive to dobutamine and hypotensive effect seems to be more often observed in adult patients than in small children.

Accordingly, the use of dobutamine in children should be monitored closely, bearing in mind these pharmacodynamic characteristics.

Dobutamine stress echocardiography (Adult population only)

Because of possible life-threatening complications, the administration of dobutamine for stress echocardiography should only be undertaken by a physician with sufficient personal experience of the use of dobutamine for this indication.

Cardiac rupture is a potential complication of myocardial infarction. The risk of cardiac rupture (septal and free wall) may be influenced by a variety of factors including site of, and time since, infarct. There have been very rare, fatal reports of acute cardiac rupture during dobutamine stress testing. These events have occurred during pre-discharge examination in patients hospitalised with recent (within 4-12 days) myocardial infarction. In the reported cases of free wall rupture, resting echocardiogram showed a dyskinetic and thinned inferior wall. Patients considered at risk of cardiac rupture during dobutamine testing should therefore be carefully evaluated prior to testing.

Dobutamine stress echocardiography must be discontinued if one of the following diagnostic endpoints occurs:

- reaching the age-predicted maximal heart rate [(220-age in years)x0.85],

- systolic blood pressure decrease greater than 20 mmHg,

- blood pressure increase above 220/120 mmHg,

- progressive symptoms (angina pectoris, dyspnoea, dizziness, ataxia),

- progressive arrhythmia (e.g. coupling, ventricular salvos),

- progressive conduction disturbances,

- recently developed wall motility disorders in more than 1 wall segment (16-segment model),

- increase of endsystolic volume,

- development of repolarisation abnormality (due to ischaemia horizontal or down sloping ST segment depression more than 0.2 mV at an interval of 80 (60) ms after the J point compared to baseline, progressive or monophasic ST segment elevation above 0.1 mV in patients without a previous myocardial infarction,

- reaching peak dose.

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 be only 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 serious complications (see section 4.8) dobutamine stress echocardiography must be stopped immediately.

Dobutamine contains sodium metabisulfite (E223), which may rarely cause allergic reactions (hypersensitivity) and asthma-like symptoms (bronchospasm).

After termination of infusion, patients must be monitored until stabilised.

4.5. Interaction with other medicinal products and other forms of interaction

Via competitive receptor inhibition, the sympathomimetic effect of dobutamine can be reduced by simultaneous administration of a beta receptor blocker. In addition, the alpha agonistic effects may cause peripheral vasoconstriction with a consequent increase in blood pressure.

With simultaneous alpha-receptor blockade, the predominating beta-mimetic effects may cause tachycardia and peripheral vasodilatation.

Simultaneous administration of dobutamine and primarily venous acting vasodilators (e.g. nitrates, sodium nitroprusside) may cause a greater increase of cardiac output as well as a more pronounced decrease of peripheral resistance and ventricular filling pressure than administration of one of the individual substances alone.

Administering dobutamine to diabetic patients may cause increased insulin demand. In diabetic patients insulin levels should be checked when starting dobutamine therapy changing the rate of infusion and discontinuing the infusion. If necessary the insulin dose must be adjusted as required.

Simultaneous administration of high doses of dobutamine with ACE inhibitors (e.g. captopril) may cause an increase in cardiac output, accompanied by increased myocardial oxygen consumption. Chest pain and rhythm disturbances have been reported in this context.

Dobutamine combined with dopamine causes – depending on the dopamine dosage and in contrast to its sole administration – a more distinct increase of blood pressure as well as a decrease or no change of ventricular filling pressure.

Sodium metabisulfite is a very reactive compound. It must therefore be assumed that thiamine (vitamin B1) co-administered with the preparation is catabolised.

Caution should be exercised when administering dobutamine with inhaled anaesthetics, since, concomitant use may increase the excitability of the myocardium and the risk of ventricular extrasystoles.

The effects of dobutamine may be potentiated with concomitant use of entacapone.

Dobutamine stress echocardiography

In the case of anti-anginal therapy, in particular heart rate lowering agents like beta-blockers, the ischaemic reaction to stress is less pronounced or may be nonexistent.

Therefore anti-anginal therapy may need to be withheld for 12 hours prior to dobutamine stress echocardiography.

When adding atropine at the highest titration level of dobutamine:

Due to the prolonged duration of the stress echocardiography protocol, the higher total dose of dobutamine and the simultaneous administration of atropine, there is an increased risk of adverse reactions.

4.6. Fertility, pregnancy and lactation

Pregnancy

As there is no adequate data on the safety of dobutamine in human pregnancy and it is not known whether dobutamine crosses the placenta, dobutamine should not be used during pregnancy unless potential benefits outweigh the potential risks to the foetus and there are no safer therapeutic alternatives.

Breastfeeding

It is not known, whether dobutamine is excreted in breast milk, so caution should be exercised. If treatment with dobutamine is required for the mother during lactation, breast feeding should be discontinued for the duration of treatment.

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

Evaluation of undesirable effects is based on the following frequency scale:

Very common: ≥ 1/10

Common:

Uncommon:

Rare:

Very rare:

Not known:

≥ 1/100 to < 1/10

≥ 1/1 000 to < 1/100

≥ 1/10 000 to < 1/1 000

< 1/10 000

cannot be estimated from the available data

Blood and lymphatic system disorders

Common:

Eosinophilia, inhibition of thrombocyte aggregation (only when continuing infusion over a number of days).

Immune system disorders

Common:

Uncommon:

Hypersensitivity reactions including rash and eosinophilic myocarditis have been reported.

Sodium metabisulfite may cause allergic reactions including anaphylaxis, life-threatening or minor asthmatic attacks (see section 4.4).

Metabolism and nutrition disorders

Very rare:

Hypokalaemia.

Nervous system disorders

Common:

Very rare:

Headache.

Myoclonus has been reported in patients with severe renal failure receiving dobutamine.

Cardiac disorders / Vascular disorders

Very common:

Common:

Uncommon:

Very rare:

Not known:

Increase of the heart rate by ≥ 30 beats/min.

Blood pressure increase of ≥ 50 mmHg. Patients suffering from arterial hypertension are more likely to have a higher blood pressure increase.

Blood pressure decrease, ventricular dysrhythmia, dose-dependent ventricular extrasystoles.

Increased ventricular frequency in patients with atrial fibrillation.

These patients should be digitalised prior to dobutamine infusion.

Vasoconstriction in particular in patients who have previously been treated with beta blockers.

Anginal pain, palpitations.

Ventricular tachycardia, ventricular fibrillation, atrial fibrillation.

Bradycardia, myocardial ischaemia, myocardial infarction, cardiac arrest.

Decrease in pulmonary capillary pressure.

Paediatric population

The undesirable effects include elevation of systolic blood pressure, systemic hypertension or hypotension, tachycardia, headache, and elevation of pulmonary wedge pressure leading to pulmonary congestion and edema, and symptomatic complaints.

Dobutamine stress echocardiography

Cardiac disorders / Vascular disorders

Very common:

Common:

Uncommon:

Very rare:

Not known:

Pectoral anginal discomfort, ventricular extra-systoles with a frequency of > 6/min, electrocardiogram ST segment elevation.

Supraventricular extrasystoles, ventricular tachycardia.

Ventricular fibrillation, myocardial infarction, atrial fibrillation, left ventricular outflow tract obstruction.

Occurrence of second degree atrioventricular block, coronary vasospasms. Fatal cardiac rupture (see section 4.4).

Hypertensive/hypotensive blood pressure decompensation, occurrence of intracavitary pressure gradients, palpitations.

Stress cardiomyopathy (Takotsubo syndrome) (see section 4.4).

Respiratory, thoracic and mediastinal disorders

Common:

Bronchospasm, shortness of breath.

Gastrointestinal disorders

Common:

Nausea.

Skin and subcutaneous tissue disorders

Common:

Very rare:

Exanthema.

Petechial bleeding.

Musculoskeletal and connective tissue disorders

Common:

Chest pain.

Renal and urinary disorders

Common:

Increased urgency at high dosages of infusion.

General disorders and administration site conditions

Common:

Very rare:

Fever, phlebitis at the injection site.

In case of accidental paravenous infiltration, local inflammation may develop.

Cutaneous necrosis.

Further undesirable effects

Restlessness, nausea, headache, paraesthesia, tremor, urinary urgency, feeling of heat and anxiety, myoclonic spasm.

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 the 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

Symptoms of overdose

Symptoms are generally caused by excessive stimulation of beta-receptors. Symptoms may include nausea, vomiting, anorexia, tremor, anxiety, palpitations, headache, anginal pain and unspecific chest pain. The positive inotropic and chronotropic cardiac effects may cause hypertension, supraventricular/ventricular arrhythmia and even ventricular fibrillation as well as myocardial ischaemia. Hypotension may occur due to peripheral vasodilatation.

Treatment of overdose

Dobutamine is metabolised rapidly and has a short duration of effect (half-life 2 - 3 minutes).

In case of overdose, administration of dobutamine should be terminated. If necessary, resuscitation procedures must be carried out immediately. Under conditions of intensive care, vital parameters must be monitored and corrected if necessary. Balanced levels of blood gases and serum electrolytes must be maintained.

Severe ventricular arrhythmias can be treated with administration of lidocaine or a beta blocker (e. g. propranolol).

Angina pectoris should be treated with a sublingually administrated nitrate or possibly a short-acting, I.V. beta blocker (e.g. esmolol).

In case of a hypertensive reaction, dose reduction or termination of the infusion is usually sufficient.

With oral administration, the quantity absorbed from the mouth or gastrointestinal tract is unpredictable. In case of accidental oral administration, resorption may be reduced by administration of activated charcoal, which is often more effective than administration of emetics or performing gastric lavage.

The benefit of forced diuresis, peritoneal dialysis, haemodialysis or haemoperfusion via activated charcoal has not been demonstrated for cases of dobutamine overdosage.

Dobutamine stress echocardiography

If applying one of the common dosage schemes, toxic doses are not reached, not even cumulatively. In case of severe complications during diagnostic administration of dobutamine, the infusion must be terminated at once and sufficient oxygen supply and ventilation must be guaranteed. Treatment of angina pectoris should be performed with an intravenous beta-blocker with a very short-acting effect. Angina pectoris may also be treated with a sublingually administered nitrate, if necessary. Class I and III antiarrhythmics must not be administrated.