SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Dopacard 50mg/5ml Concentrate for Solution for Infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Dopexamine hydrochloride as a 1% solution (w/v). Each 5 ml ampoule contains 50 mg of dopexamine hydrochloride.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Concentrate for solution for infusion.

The solution is clear and colourless, with pH 2.2 - 2.8.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Dopacard is indicated for short-term intravenous administration to patients in whom afterload reduction, (through peripheral vasodilatation, and/or renal and mesenteric vasodilatation), combined with a mild positive inotropic effect is required for the treatment of exacerbations of chronic heart failure, or heart failure associated with cardiac surgery.

4.2 Posology and method of administration

For intravenous use only.

Dopacard must be diluted before use. For instructions on dilution of the product before administration, see section 6.6.

Adults and the elderly:

Infusion should begin at a dose of 0.5 microgram/kg/min and may be increased to 1 microgram/kg/min and then in increments (0.5-1 microgram/kg/min) up to 6 micrograms/kg/min at not less than 15 minute intervals according to the patient’s haemodynamic and clinical response. Smaller increments (0.5 microgram/kg/min) may be justified in certain patients according to haemodynamic and clinical response.

Children:

The safety and efficacy of Dopacard for use in children have not been established.

Administration

Dopacard should only be administered intravenously by infusion through a cannula or catheter in a central or large peripheral vein. Contact with metal parts in infusion apparatus should be minimised. A device which provides accurate control of the rate of flow is essential.

Central administration: Dopacard can be administered via a cannula or catheter sited in a central vein. The concentration of the infusion solution for administration via this route must not exceed 4mg/ml.

Peripheral administration: Dopacard can be administered via a cannula in a large peripheral vein. The concentration of the infusion solution for administration via this route must not exceed 1mg/ml. Thrombophlebitis has been reported with peripheral administration using concentrations of Dopacard exceeding 1mg/ml.

During the administration of Dopacard, as with any parenteral catecholamine, the rate of administration and duration of therapy should be adjusted according to the patient’s response as determined by heart rate and rhythm (ECG), blood pressure, urine flow and, whenever possible, measurement of cardiac output.

It is recommended that the infusion of Dopacard is reduced gradually rather than withdrawn abruptly.

The duration of therapy is dependent upon the patient’s overall response to treatment. Extended therapy beyond 48 hours has not been fully evaluated.

4.3 Contraindications

Known hypersensitivity to dopexamine hydrochloride or excipients (disodium edetate).

Patients who are receiving monoamine oxidase inhibitors (MAOIs).

Phaeochromocytoma.

Thrombocytopenia.

Patients with left ventricular outlet obstruction such as hypertrophic obstructive cardiomyopathy or aortic stenosis. In such patients, positive inotropic activity may increase left ventricular outflow obstruction and sudden vasodilatation may cause hypotension.

4.4 Special warnings and precautions for use

Dopacard should not be administered to patients with severe hypotension or a markedly reduced systemic vascular resistance until specific resuscitative measures have been taken to restore blood pressure to a clinically acceptable level.

Benign arrhythmias such as ventricular premature beats and, more rarely, serious arrhythmias have been reported in some patients. If excessive tachycardia occurs during Dopacard administration, then a reduction or temporary discontinuation of the infusion should be considered.

In patients with a marked reduction in systemic vascular resistance, Dopacard should not be used as a direct substitute for pressor agents or other inotropes.

As with other catecholamines, Dopacard should be administered with caution to patients with a clinical history of ischaemic heart disease especially following acute myocardial infarction or recent episodes of angina pectoris as a tachycardia may increase myocardial oxygen demand and further exacerbate myocardial ischaemia.

Correction of hypovolaemia must be achieved prior to administration of Dopacard. Hypovolaemia should also be corrected during therapy as vasodilatation occurs due to treatment.

Care should be exercised so as to restrict the sodium and fluid load during administration of Dopacard.

Care must be exercised when administering Dopacard in the presence of hypokalaemia or hyperglycaemia. In common with other B₂-agonists, Dopacard depresses plasma potassium and raises plasma glucose. These effects are minor and reversible.

Monitoring of potassium and glucose is advisable in patients likely to be at risk from such changes, e.g. diabetics, patients with myocardial infarction or patients being treated with diuretics or cardiac glycosides.

As has been observed with other B₂-adrenergic agonists, a small reversible fall in circulating platelet numbers has been observed in some patients. No adverse effects attributable to alterations in platelet count have been seen in clinical studies.

As with other parenteral catecholamines, there have been occasional reports of partial tolerance, with some attenuation of the haemodynamic response developing during long-term infusions of Dopacard.

The risk of thrombophlebitis and local necrosis may be increased if the concentration of Dopacard administered via a peripheral vein exceeds 1 mg/ml. Thrombophlebitis is rare when the concentration of drug used for peripheral administration is less than 1 mg/ml.

4.5 Interaction with other medicinal products and other forms of interaction

As Dopacard inhibits the Uptake-1 mechanism, it may potentiate the effects of exogenous catecholamines such as noradrenaline. Caution is recommended when these agents are administered concomitantly with Dopacard or soon after its discontinuation.

There is no evidence of an interaction with dopamine, other than possible attenuation of the indirect sympathomimetic inotropic effects of higher doses of dopamine due to Uptake-1 blockade by Dopacard.

Concomitant use with B₂-adrenergic and dopamine receptor antagonists requires caution since possible attenuation of the pharmacological effects of Dopacard may occur.

4.6 Pregnancy and lactation

There is no experience of the use of Dopacard in pregnant or lactating women and therefore its safety in these situations has not been established. There is insufficient evidence from animal studies to indicate it is free from hazard.

Therefore Dopacard is not recommended for use in pregnant or lactating women.

4.7    Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed.

4.8    Undesirable effects

Careful titration of the dose may minimise the incidence of adverse events.

Tachycardia is the most common undesirable effect reported with Dopacard administration in studies of use in heart failure. The increases in heart rate are dose-related and, in most cases, not clinically significant.

Hypertension and transient hypotension have been reported after cardiac surgery with a common frequency. These events, however, are not uncommon as compensatory mechanisms following cardiac surgery.

A full list of adverse reactions reported with Dopacard during clinical studies and post marketing experience is shown in the tables below. Adverse reactions are listed below as MedDRA preferred term by system organ class and frequency (frequencies are defined as: very common >1/10, common >1/100 to <1/10, uncommon > 1/1,000 to <1/100, not known (cannot be estimated from the available data):

Table 1: Adverse reactions experienced by patients receiving Dopexamine from all heart failure studies

System Organ Class	Frequency	Undesirable effects
Nervous system disorders	Common	Tremor, headache
Cardiac disorders	Very common	Tachycardia
	Common	Premature ventricular contractions (PVCs), atrial fibrillation and ventricular tachycardia, asystole and angina
Vascular disorders	Common	Transient hypotension
Respiratory, thoracic and mediastinal disorders	Common	Dyspnoea
Gastrointestinal disorders	Very common	Nausea
	Common	Vomiting
Skin and subcutaneous tissue disorders	Common	Hyperhidrosis

Table 2: Adverse reactions experienced by patients receiving Dopexamine in cardiac surgery studies

System Organ Class	Frequency	Undesirable effects
Infections and infestations	Common	Sepsis
Cardiac disorders	Common	Sinus and nodal bradycardia, cardiac arrest, myocardial infarction, cardiac enzyme

		changes, non-specific ECG changes
Vascular disorders	Common	Hypertension, haemorrhage
Respiratory, thoracic and mediastinal disorders	Common	Respiratory failure, acute respiratory distress syndrome (ARDS), pulmonary oedema, pulmonary hypertension
Renal and urinary disorders	Common	Renal failure

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.

4.9 Overdose

The half-life of Dopacard in blood is short (see section 5.2). Consequently, the effects of overdosage are likely to be short-lived provided that administration is discontinued. However, in some cases, it may be necessary to initiate prompt supportive measures.

Effects of overdosage are likely to be related to the pharmacological actions and include tachycardia, bradycardia, myocardial infarction, arrhythmias, tremulousness and tremor, nausea and vomiting, headache, sweating, shortness of breath and anginal pain.

Management should be symptomatic and supportive. Stop the dopexamine infusion until symptoms settle and heart rate and blood pressure return to normal. In asymptomatic patients monitor heart rate and blood pressure for at least 30 minutes. Consider esmolol, metoprolol, or other beta-adrenergic blocking agents for cardiac dysrhythmias.

5 PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: Adrenergic and dopaminergic agents; ATC code: C01CA14

The primary actions of Dopacard (dopexamine hydrochloride) are the stimulation of adrenergic B2-receptors and peripheral dopamine receptors of DAi and DA₂ subtypes. In addition, Dopacard is an inhibitor of neuronal reuptake of noradrenaline (Uptake-1). These pharmacological actions result in an increase in cardiac output mediated by afterload reduction (B₂, DA₁) and mild positive inotropism (B₂, Uptake-1 inhibition) together with an increase in blood flow to vascular beds (DA₁) such as the renal and mesenteric beds. Dopacard therefore provides an increase in systemic and regional oxygen delivery. Dopacard is not an a-adrenergic agonist and does not cause vasoconstriction and is not a pressor agent.

5.2    Pharmacokinetic properties

Dopacard is rapidly eliminated from blood with a half-life of approximately 6-7 minutes in healthy volunteers and around 11 minutes in patients with cardiac failure. Subsequent elimination of the metabolites is by urinary and biliary excretion. The response to Dopacard is rapid in onset and effects subside rapidly on discontinuation of the infusion.

5.3    Preclinical safety data

There is no information relevant to the prescriber, which has not been included in other sections of this Summary of Product Characteristics.

6 PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Disodium edetate Hydrochloric acid Water for Injections.

6.2    Incompatibilities

Dopacard should not be added to sodium bicarbonate or any other strongly alkaline solutions as inactivation will occur.

Dopacard should not be mixed with any other medicinal products before administration except those mentioned in section 6.6..

Contact with metal parts, in infusion apparatus for example, should be minimised.

6.3    Shelf Life

The shelf life of unopened ampoules is 3 years.

Prepared intravenous solutions in 0.9% Sodium Chloride Injection or 5% Dextrose Injection are stable for 24 hours at room temperature.

From a microbiological point of view, the product should be diluted and used immediately after opening. 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 8°C, unless dilution has taken place in controlled and validated aseptic conditions.

6.4    Special Precautions for Storage

Store below 25°C.

Keep the ampoule in the outer carton in order to protect from light and moisture.

For storage of sterile products that have been opened, diluted or reconstituted see section 6.3.

6.5 Nature and contents of container

Box of 10 clear glass ampoules each containing 5ml of 1% (w/v) solution of dopexamine hydrochloride (50mg per ampoule).

6.6 Special precautions for disposal and other handling

Dopacard should only be diluted with 0.9% Sodium Chloride Injection, 5% Dextrose Injection, Hartmann's Solution (Compound Sodium Lactate Intravenous Infusion) or Dextrose 4%/Saline 0.18% Injection.

The appropriate volume of diluent solution should be aseptically extracted from the infusion bag, or the metering chamber of the administration set, before adding the contents of the Dopacard ampoule(s) to arrive at the final concentration - see table below.