SUMMARY OF PRODUCT CHARACTERISTICS
Резюме качества продукта

(INTERNATIONAL VERSION)
(Интернациональная версия)

 

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 dobutamine.

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 window.

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 volume

Dosage range		Rate in ml/hour (ml/min)
		Patient weight
		50 kg	70 kg	90 kg
Low	ml/hour	1.5	2.1	2.7
2.5 µg/kg/min	(ml/min)	(0.025)	(0.035)	(0.045)
Moderate	ml/hour	3.0	4.2	5.4
5 µg/kg/min	(ml/min)	(0.05)	(0.07)	(0.09)
High	ml/hour	6.0	8.4	10.8
10 µg/kg/min	(ml/min)	(0.10)	(0.14)	(0.18)

 

Dosages for continuous infusion apparatus:
1 injection vial of 250 mg dobutamine to 500 ml solution volume

Dosage range		Rate in ml/hour (ml/min)
		Patient weight
		50 kg	70 kg	90 kg
Low	ml/hour	15	21	27
2.5 µg/kg/min	(ml/min)	(5)	(7)	(9)
Moderate	ml/hour	30	42	54
5 µg/kg/min	(ml/min)	(10)	(14)	(18)
High	ml/hour	60	84	108
10 µg/kg/min	(ml/min)	(20)	(28)	(36)

* 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.

4.3. Contraindications
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 (MAOI).

4.4. Special warnings and special precautions for use
Hypovolaemia should be corrected before treatment with dobutamine is instituted.
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 blockade.
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
Not applicable.

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 rarely.
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 with ß-blockers.
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 isolated cases.
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.

4.9. Overdose
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

5.1. Pharmacodynamics
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.

Dobutamine:
•  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 be excluded.

Pharmacological tolerance may occur after 72 hours of continuous infusion, probably by a reduced activation capacity of the adenyl cyclase system.

5.2. Pharmacokinetics
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
Acute toxicity:
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 performed.

Reproduction toxicity:
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.

Local tolerance:
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
•  sodium chloride
•  citric acid monohydrate
•  water for injection
•  sodium hydroxide

6.2. Incompatibilities
Do not add Dobutamin Admeda to 5% sodium bicarbonate or any other strongly alkaline solution. Because 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:
•  Acyclovir
•  Alteplase
•  Aminophylline
•  Bretylium
•  Calcium chloride
•  Calcium gluconate
•  Cefamandole formiate
•  Cephalothin sodium
•  Dacarbazine
•  Diazepam
•  Digoxin
•  Ethacrylic acid (sodium salt)
•  Furosemide
•  Heparin sodium
•  Hydrocortisone sodium succinate
•  Insulin
•  Potassium chloride
•  Magnesium sulphate
•  Penicillin
•  Phenytoin
•  Streptokinase
•  Verapamil
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	18 months
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 *	24 hours
Storage at RT with glucose *	24 hours
Storage at RT with Ringer's lactate *	24 hours

*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
See 4.2

7. Marketing Authorization Holder
Admeda Arzneimittel GmbH
Trift 4
D-23863 Nienwohld

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
July, 2002