Dobutamine 12.5mg/Ml Sterile Concentrate
SUMMARY OF PRODUCT CHARACTERISTICS 1 NAME OF THE MEDICINAL PRODUCT
Dobutamine 12.5mg/ml Sterile Concentrate
2 QUALITATIVE AND QUANTITATIVE COMPOSITION
Each 20ml solution contains Dobutamine Hydrochloride equivalent to 250mg dobutamine .
For the full list of excipients, see section 6.1 3. PHARMACEUTICAL FORM
Concentrate for solution for infusion.
Clear, colourless or almost colourless sterile aqueous solution intended for intravenous infusion to human beings after dilution with a suitable diluent.
4.1 Therapeutic indications Adult population
Dobutamine is indicated for adults who require inotropic support in the treatment of low output cardiac failure associated with myocardial infarction, open heart surgery, cardiomyopathies, septic shock or cardiogenic shock. Dobutamine can increase or maintain cardiac output during positive end expiratory pressure (PEEP) ventilation.
Dobutamine stress echocardiography (Adult population only)
Dobutamine may also be used as an alternative to exercise for cardiac stress testing in patients for whom exercise testing is impracticable. This use of dobutamine should be confined to units where exercise stress testing is routinely performed and the usual monitoring and precautions required for such testing should be applied when dobutamine is used for this purpose
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 Adult population
Dobutamine Concentrate must be further diluted to at least 50ml prior to administration in an i.v. container with one of the intravenous solutions listed below:
Sodium Chloride Intravenous Infusion BP 5% Dextrose Intravenous Infusion BP
5% Dextrose + 0.9% Sodium Chloride Intravenous Infusion BP 5% Dextrose + 0.45% Sodium Chloride Intravenous Infusion BP Sodium Lactate Intravenous infusion BP
For example, diluting to 250 or 500ml will provide the following concentrations for administration:
250ml contains 1,000 micrograms/ml of dobutamine 500ml contains 500 micrograms/ml of dobutamine.
The prepared solution should be used within 24hours
Method of Administration:
Route of administration: For intravenous use only.
Because of its short half-life, Dobutamine is administered as a continuous intravenous infusion. After dilution, it should be administered through an intravenous needle or catheter using an i.v. drip chamber or other suitable metering device to control the rate of flow.
Recommended dosage for adults, including the elderly: The usual dose range is 2.5 to 10 micrograms/kg/minute. Occasionally, a dose as low as 0.5 micrograms/kg/minute will produce a response. Rarely, up to 40 micrograms/kg/minute may be required.
The rate of administration and the duration of therapy should be adjusted according to the patient’s response as determined by heart rate, blood pressure, urine flow and, where possible, measurements of cardiac output.
When discontinuing therapy, a gradual reduction in dosage is generally advised.
Side effects are dose-related and are infrequent with infusion rates below 10 micrograms/kg/minute. Infusion rates of up to 40 micrograms/kg/minute have been used occasionally without significant adverse effects.
The final volume administered should be determined by the fluid requirement of the patient. Concentrations of up to 5,000 micrograms/ml have been used in patients on restricted fluid intake. To ensure accurate dosage, an infusion pump is required to administer high concentrations of Dobutamine.
Cardiac Stress testing (Adult population only): The recommended dose is an incremental increase of 5 micrograms/kg/minute from 5 up to 20 micrograms/kg/minute, each dose being infused for eight minutes. It is essential to monitor the ECG continuously and to terminate the infusion in the event of >3mm ST segment depression of any ventricular arrhythmia. The infusion should also be stopped if the heart rate reaches the age/sex maximum, systolic BP rises above 200mm 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 0.51.0 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 for Paediatric Use:
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.
4.3 Contraindications
• Hypersensitivity to dobutamine, sodium metabisulphite or any of the other ingredients.
• Hypovolaemia •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)
- previous experience of hypersensitivity to dobutamine
4.4 Special warnings and precautions for use
Adult population
In the event of an undue increase in heart rate or systolic blood pressure, or if an arrhythmia is precipitated, the dose of dobutamine should be reduced or the drug should be discontinued temporarily.
Dobutamine may precipitate or exacerbate ventricular ectopic activity; rarely has it caused ventricular tachycardia or fibrillation. Because dobutamine facilitates A-V conduction, patients with atrial flutter or fibrillation may develop rapid ventricular responses.
Particular care is required when administering dobutamine to patients with acute myocardial infarction, as any significant increase in heart rate or excessive increases in arterial pressure that occur may intensify ischaemia and cause anginal pain and ST segment elevation.
Inotropic agents, including dobutamine, 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.
Minimal vasoconstriction has occasionally been observed, most notably in patients recently treated with a B-blocking drug. The inotropic effect of dobutamine results from stimulation of cardiac B1 receptors and this effect is prevented by B-blocking drugs. However, dobutamine has been shown to counteract the cardiodepressive effects of B-blocking drugs. Conversely, a-adrenergic blockade may make the B1 and B2 effects apparent, resulting in tachycardia and vasodilatation.
Dobutamine stress echocardiography
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.
The use of dobutamine concentrate as an alternative to exercise for cardiac stress testing is not recommended for patients with unstable angina, bundle branch block, valvular heart disease, aortic outflow obstruction or any cardiac condition that could make them unsuitable for exercise stress testing (see section 4.3).
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) x 0.85]
- 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
In the event of serious complications (see section 4.8) dobutamine stress echocardiography must be stopped immediately.
During the administration of dobutamine concentrate, as with any 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.
Precipitous decreases in blood pressure have occasionally been described in association with dobutamine therapy. Dosage reduction or discontinuing the infusion is usually sufficient to restore baseline values, but rarely intervention may be required and reversibility may not be immediate.
Dobutamine concentrate should be used with caution in the presence of severe hypotension complicating cardiogenic shock (mean arterial pressure less than 70mm Hg).
Hypovolaemia should be corrected when necessary with whole blood or plasma before administering dobutamine.
During dobutamine therapy, if arterial blood pressure remains low or decreases progressively, despite adequate ventricular filling pressure and cardiac output, consideration may be given to the concomitant use of a peripheral vasoconstrictor drug, such as dopamine or noradrenaline.
Dobutamine Concentrate contains sodium metabisulphite. Sulphites may cause allergic-type reactions, including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people. Sulphite sensitivity is seen more frequently in asthmatic than in non-asthmatic subjects.
Caution should be taken in patient with renal failure (especially being treated for congestive cardiac failure), as myoclonus has been reported as an adverse effect of this product in such patients.
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.
4.5 Interaction with other medicinal products and other forms of interaction
Halogenated anaesthetics:
Although it is less likely than adrenaline to cause ventricular arrhythmias, dobutamine concentrate should be used with great caution during anaesthesia with cyclopropane, halothane and other halogenated anaesthetics.
Entacapone:
The effects of Dobutamine concentrate may be enhanced by entacapone. Beta-blockers:
The inotropic effect of dobutamine stems from stimulation of cardiac beta1 receptors, this effect is reversed by concomitant administration of beta-blockers. Dobutamine has been shown to counteract the effect of beta-blocking drugs. In therapeutic doses, dobutamine has mild alpha1- and beta2-agonist properties. Concurrent administration of a non-selective beta-blocker such as propranolol can result in elevated blood pressure, due to alpha-mediated vasoconstriction, and reflex bradycardia. Beta-blockers that also have alpha-blocking effects, such as carvedilol, may cause hypotension during concomitant use of dobutamine due to vasodilation caused by beta2 predominance (see section 4.4 Special warnings and precautions for use).
4.6 Fertility, pregnancy and lactation
Reproduction studies in rats and rabbit have revealed no evidence of impaired fertility, harm to the foetus or teratogenic effects due to dobutamine. As there are no adequate and well controlled studies in pregnant women and as animal reproduction studies are not always predictive of human response, Dobutamine should not be used during pregnancy unless the potential benefits outweigh the potential risks to the foetus.
As it is not known whether Dobutamine is excreted in breast milk, breastfeeding should be suspended for the duration of the treatment.
4.7 Effects on ability to drive and use machines
Not applicable.
4.8
Undesirable effects
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 concentrate for 72 hours or more; therefore, higher doses may be required to maintain the same effects.
The undesirable effects are listed according to their frequency, starting with the most common undesirable effects. The following frequency information is used: Very common (>1/10); Common (>1/100 to <1/10); Uncommon (>1/1000 to <1/100); Rare (>1/10,000 to <1/1000); Very rare (<1/10,000),
Not known (frequency could not be estimated from the available data).
Immune system disorders:
Not Known: Hypersensitivity reactions including rash, fever, eosinophilia and bronchospasm have been reported. Anaphylactic reactions and severe life-threatening asthmatic episodes may be due to sulphite sensitivity (see section
4.4 Special warnings and other precautions for use).
Blood and lymphatic system disorders
Common: Eosinophilia, inhibition of thrombocyte aggregation (only when continuing infusion over a number of days)
Metabolism and nutrition disorders
Very rare: Hypokalaemia
Nervous system disorders
Common: Headache
Not known: Paraesthesia, tremor, myoclonic spasm. Myoclonus has been reported in patients with severe renal failure receiving Dobutamine
Cardiac disorders / vascular disorders
Very common: Increase of the heart rate by > 30 beats/min
Common: 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 receptor blockers. Anginal pain, palpitations
Uncommon: Ventricular tachycardia, ventricular fibrillation
Very rare: Bradycardia, myocardial ischaemia, myocardial infarction, cardiac
arrest
Not known: Electrocardiogram ST segment elevation Decrease in pulmonary capillary pressure
Eosinophilic myocarditis has been noted in explanted hearts of patients who had undergone treatment with multiple medications including dobutamine or other inotropic agents prior to transplantation.
Children: pronounced increase of heart rate and/or blood pressure as well as a lower decrease of the pulmonary capillary pressure than adults. Increase of pulmonary capillary pressure in children under 1.
Gastrointestinal disorders
Not known: Nausea
Psychiatric disorders
Not known: Restlessness, feeling of heat and anxiety
Renal and urinary disorders
Not known: Urinary urgency
Dobutamine stress echocardiography Cardiac disorders / vascular disorders
Very common: Pectoral anginal discomfort, ventricular extra-systoles with a frequency of > 6/min
Common: Supraventricular extrasystoles, ventricular tachycardia
Uncommon: Ventricular fibrillation, myocardial infarction
Very rare: Occurrence of a second degree atrioventricular block, coronary
vasospasms.
Hypertensive/hypotensive blood pressure decompensation, occurrence of an
intracavitary pressure gradient, palpitations
Not known: Stress cardiomyopathy
Left ventricular outflow tract obstruction
Fatal cardiac rupture
Respiratory system, thoracic and mediastinal disorders
Common: Bronchospasm, shortness of breath
Gastrointestinal disorders
Common: Nausea
Skin and subcutaneous tissue disorders
Common: Exanthema Very rare: 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: Fever, phlebitis at the injection site
In case of accidental paravenous infiltration, local inflammation may develop. Very rare: Cutaneous necrosis
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.
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
Website: www.mhra.gov.uk/yellowcard
4.9 Overdose
Overdose of Dobutamine have been reported rarely. The symptoms of toxicity may include anorexia, nausea. vomiting, tremor, anxiety, palpitations, headache, shortness of breath and anginal and non specific chest pain. The positive inotropic and chronotropic effects of Dobutamine may cause hypertension, tachyarrhythmias, myocardial ischaemia and ventricular fibrillation. Hypotension may result from vasodilatation.
The duration of action of Dobutamine hydrochloride is generally short (halflife, approximately 2 minutes). Dobutamine infusion should be temporarily discontinued until the patient’s condition stabilises. The patient should be monitored and any appropriate resuscitative measures initiated promptly.
Forced diuresis, peritoneal dialysis, haemodialysis or charcoal haemoperfusion have not been established as beneficial.
If the product is ingested, unpredictable absorption may occur from the mouth and gastrointestinal tract.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Dobutamine is synthetic sympathomimetic agent. It is a direct-acting and the primary mode of action of Dobutamine is to increase cardiac contractility by stimulating the \ receptors of the heart.
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-methyl transferase to an inactive compound, 3-0-methydobutamine and by conjugation with glucuronic acid. Conjugates of dobutamine and 3-0-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
No further relevant information other than that which is included in other sections of the Summary of Product Characteristics.
6
PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Sodium Metabisulphite Hydrochloric Acid 10% w/v Sodium Hydroxide 10% w/v q.s Water for Injections
6.2 Incompatibilities
Do not add Dobutamine Concentrate to 5% Sodium Bicarbonate Intravenous Infusion BP 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 Concentrate should not be used with other agents or other diluents containing both sodium metabisulphite and ethanol. Solutions containing Dobutamine Hydrochloride may turn pink; the colour may turn pink; the colour may intensify with time. This colour change is due to slight oxidation of the drug, but there is no significant loss of potency during the recommended storage period.
6.3 Shelf life
2 years.
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 2-8°C unless reconstitution/dilution (etc) has taken place in controlled and validated aseptic conditions.
6.4 Special precautions for storage
Do not store above 25°C.
Keep the container in the outer carton in order to protect from light.
6.5 Nature and contents of container
20ml clear One point cut (OPC) glass ampoules, glass type 1. Ph.Eur Packs of 1, 5 or 10 ampoules
Special precautions for disposal and other handling
6.6.
The carton label stated the following:
The solution must be diluted before use.
Do not dilute with alkaline solutions.
Dilute to at least 50ml before administration by intravenous infusion. Use as directed by the physician.
Keep out of sight and reach of children.
If only part used, discard the remaining solution.
Please refer to 4.2 Posology and method of Administration for details on instructions for use/handling.
7 MARKETING AUTHORISATION HOLDER
Mercury Pharma International Ltd 4045, Kingswood Road,
City West Business Park,
Co Dublin, Ireland
8. MARKETING AUTHORISATION NUMBER
PL 02848/0180
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
3 November 1999
10 DATE OF REVISION OF THE TEXT
07/04/2015