STERILE DOBUTAMINE HYDROCHLORIDE SOLUTION 250 MG IN 20ML - summary of medicine characteristics

Sterile Dobutamine Hydrochloride Solution 250mg in 20ml.

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Dobutamine hydrochloride 1.4% w/v equivalent to dobutamine 1.25% w/v.

3 PHARMACEUTICAL FORM

Clear colourless sterile solution intended for parenteral administration after dilution.

4.1 Therapeutic indications

Sterile dobutamine hydrochloride solution is indicated in adults who require inotropic support in the treatment of low output cardiac failure associated with cardiomyopathies, cardiogenic or septic shock, myocardial infarction and cardiac surgery. Dobutamine can increase or maintain cardiac output during positive end expiratory pressure (PEEP) ventilation.

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

4.2 Posology and method of administration

This is a potent drug. The solution must be diluted to at least 50ml before administration and may then be administered by intravenous infusion.

Alkaline solutions such as 5% sodium bicarbonate should not be added to dobutamine hydrochloride because the drug will be inactivated.

Sterile dobutamine hydrochloride solution must be diluted to at least 50ml with one of the following intravenous solutions:

Sodium chloride intravenous infusion BP 0.9% w/v

Dextrose intravenous infusion BP 5% w/v

5% dextrose and 0.9% sodium chloride intravenous infusion

BP

5% dextrose and 0.45% sodium chloride intravenous infusion BP Sodium lactate intravenous infusion BP.

If not required immediately, the diluted solution may be stored for up to 24 hours in a refrigerator. Dobutamine should be administered as a continuous infusion because of its short half-life.

A suitable metering device is required in the infusion system to control the rate of flow and this should be adjusted to the optimum patient response and monitored constantly in the light of the individual patient's response.

Recommended dosage for adults and the elderly:

The usual dose is 2.5 to 10 micrograms/kg/mi­nute. Occasionally, however, a dose as low as 0.5 microgram­s/kg/minute will elicit a response. Up to 40 micrograms/kg/mi­nute may occasionally be required.

The rate of administration and duration of therapy should be adjusted according to the patient's response as determined by heart rate, blood pressure, urine flow and, if possible, measurement of cardiac output.

It is advisable to reduce the dosage of dobutamine hydrochloride gradually rather than abruptly stopping therapy.

Side-effects which are dose related, are infrequent when dobutamine hydrochloride is administered at rates below 10 micrograms/kg/mi­nute. Rates as high as 40 micrograms/kg/mi­nute have been used occasionally without significant adverse effects.

The final volume administered should be determined by the fluid requirements of the patient. Concentrations as high as 5,000 micrograms/ml have been used in patients on a restricted fluid intake. High concentrations of dobutamine should be given with an infusion pump, to ensure accurate dosage.

Cardiac stress testing : when used as an alternative to exercise for cardiac stress testing 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 8 minutes. Continuous ECG monitoring is essential and the infusion terminated in the event of >3mm ST segment depression or any ventricular arrhythmia. The infusion should be also be terminated if heart rate reaches the age/sex maximum, systolic blood pressure rise above 220mm HG or any side effects occur.

Children : the safety and efficacy of dobutamine hydrochloride therapy in children have not been established.

Method of administration: intravenous infusion.

4.3 Contraindi­cations

Hypersensitivity to dobutamine, sodium metabisulphite or any of the other ingredients.

Phaeochromocyto ma.

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

4.4 Special warnings and precautions for use

The dose of dobutamine should be reduced or the drug should be discontinued temporarily if an undue increase in heart rate or systolic blood pressure occurs or if an arrhythmia is precipitated. 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.

Dobutamine should only be used with great care in patients with acute myocardial infarction because any significant increase in heart rate or excessive increase 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 P-blocking drug. The inotropic effect of dobutamine stems from stimulation of cardiac P1 receptors and this effect is prevented by P-blocking drugs. However, dobutamine has been shown to counteract the cardiodepressive effects of P-blocking drugs. Conversely, adrenergic blockade may make the P1 and P2 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 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.

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, 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, decreasing the dose or discontinuing the infusion typically results in rapid return of blood pressure to base-line values, but rarely intervention may be required and reversibility may not be immediate.

Dobutamine should be used with caution in the presence of severe hypotension complicating cardiogenic shock (mean arterial pressure less than 70mm HG).

If hypovolaemia is present it should be corrected by administration of either whole blood or plasma before using dobutamine hydrochloride.

If arterial blood pressure remains low or decreases progressively during administration of dobutamine despite adequate ventricular filling pressure and cardiac output, consideration may be given to the concomitant use of a peripheral vasoconstrictor agent, such as dopamine or noradrenaline.

Sterile dobutamine hydrochloride 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 people.

Also, the carton text shall contain the following statements: "Dilute to at least 50ml before use.

If not required immediately, the diluted solution may be stored for up to 24 hours in a refrigerator.

Keep out of the reach of children.

If only part used, discard the remaining solution.

Store below 21°C."

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 solution should be used with great caution during anaesthesia with cycloproprane, halothane and other halogenated anaesthetics.

Entacapo ne:

The effects of Dobutamine solution 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 betablockers. Dobutamine has been shown to counteract the effect of betablocking 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

Animal studies have not revealed any evidence of teratogenic effects from dobutamine hydrochloride. As animal reproduction studies are not always predictive of human response, the drug should not be used in pregnancy unless, in the opinion of the physician, the expected therapeutic benefits outweigh the potential risk to the foetus.

4.7 Effects on ability to drive and use machines

Not applicable in view of the indications for use and the short half-life of the drug.

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 solution for 72 hours or more; therefore, higher doses may be required to maintain the same effects.

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

Immune        system

disorders:

Not Known:

Hypersensitivity reactions including rash, fever, eosinophilia and bronchospasm, have been reported. Anaphylactic reactions and severe lifethreatening 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

Consideration should be given to monitoring serum potassium.

Cardiac

transplantation.

Vascular disorders:

Hypotension (see sections 4.4 Special warnings and precautions for use, 4.5

Interactions)

Gastrointestinal disorders

Psychiatric disorders

Renal and urinary disorders

Dobutamine stress echocardiography

Cardiac disorders / vascular disorders

Respiratory system, thoracic and mediastinal disorders

Gastrointestinal disorders

Skin and subcutaneous tissue disorders

Musculoskeletal and connective tissue disorders

Renal and urinary disorders

General disorders and administration site conditions

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

4.9 Overdose

Overdoses 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.

Because the half life of dobutamine is only about 2 minutes adverse effects may be corrected by discontinuing or reducing the rate of infusion as appropriate. 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 gastro-intestinal tract.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Dobutamine directly stimulates P1 adrenergic receptors and is generally considered a selective P1-adrenergic agonist, but the mechanisms of action of the drug are complex. It is believed that the P—adrenergic effects result from stimulation of adenyl cyclase activity. In therapeutic doses, dobutamine also has mild P2 and «-adrenergic receptor agonist effects, which are relatively balanced and result in minimal net direct effect on system vasculature. Unlike dopamine, dobutamine does not cause release of endogenous norepinephrine. The main effect of therapeutic doses of dobutamine is cardiac stimulation. While the positive inotopic effect of drug on the myocardium appears to be mediated principally via P1-adrenergic stimulation. Experimental evidence suggests that «1 adrenergic stimulation may also be involved and that the «1. adrenergic activity results mainly from the (-) stereoisomer of the drug.

The P1-adrenergic effects of dobutamine exert a positive inotopic effect on the myocardium and result in an increase in cardiac output due to increased myocardial contractility and stroke volume in healthy individuals and in patients with congestive heart failure. 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.

Electrophysiologic studies have shown that dobutamine facilitates atrioventricular conduction and shortens or causes no important change in intraventricular 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. Unlike dopamine, dobutamine does not seem to affect dopaminergic receptors and causes no renal or mesenteric vasodilation, however, urine flow may increase because of increased cardiac output.

5.2 Pharmacokinetic properties

Absorption

Orally administered dobutamine is rapidly metabolised in the gastro-intestinal 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.

5.3 Preclinical safety data

None stated.

6.1

Sodium metabisulphite and water for injection.

6.2 Incompatibilities

Incompatible with alkaline solutions such as 5% sodium bicarbonate intravenous infusion.

6.3 Shelf life

36 months.

6.4 Special precautions for storage

Protect from light. Store below 21°C.

6.5 Nature and contents of container

20ml clear glass ampoule hermetically sealed under flame at the gauging point. The ampoules are packed in cartons to contain 1, 5 or 10 ampoules.

6.6 Special precautions for disposal

Must be diluted to at least 50ml with one of the intravenous solutions listed in Section 4.2 Posology and Method of Administration before use. If not required immediately, the diluted solution may be stored for up to 24 hours in a refrigerator. If only part used, discard the remaining solution.

7 MARKETING AUTHORISATION HOLDER

Ennogen Pharma Limited

Unit G4,

Riverside Industrial Estate,

Riverside Way,

Dartford

DA1 5BS

UK