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Logo CARDIJECT 250 (Powder for Injection)

SCHEDULING STATUS:
S4

PROPRIETARY NAME
(and dosage form):

CARDIJECT 250 (Powder for Injection)

COMPOSITION:
Each vial contains
dobutamine hydrochloride equivalent to 250 mg dobutamine.

PHARMACOLOGICAL CLASSIFICATION
A.6.1 Cardiac Stimulants.

PHARMACOLOGICAL ACTION
Dobutamine is a sympathomimetic with both alpha- and beta-agonist properties; it displays a considerable selectivity for beta
1-cardiac receptors.
The primary action of dobutamine is to augment cardiac contractility by direct effects on the beta1receptorsof the heart. Its action does not seem to be a result of release of norepinephrine fromsympathetic nerve endings, nor is it exerted via dopaminergic receptors.
Cardiovascular effects
Dobutamine has relatively more prominent inotropic than chronotropic effects on the heart comparedwith isoproterenol. The inotropic action of dobutamine on the heart is associated with less cardiac-accelerating effects than that of isoproterenol; however, enhancement of atrioventricular andintraventricular conduction is similar for the two agents.
Pharmacokinetics
The onset of action is within one to two minutes. The peak effect of a particular dose may not bereached for ten minutes.
Dobutamine is rapidly inactivated with a plasma half-life of about two minutes. Conjugates ofdobutamine and its major metabolite 3-O-methyl-dobutamine are excreted primarily in urine, withsmall amounts eliminated in the faeces. The main routes of metabolism are methylation of the catecholand conjugation of dobutamine. The 3-O-methyl derivative of dobutamine is inactive.
In patients with depressed cardiac function, both dobutamine and isoproterenol increase the cardiaccontractility to a similar degree. Cardiac output is a function of stroke volume and heart rate.
Dobutamine improves the cardiac output primarily by increasing stroke volume.
Systemic vascular resistance usually decreases at all dose levels of dobutamine. The pulse pressure is widened because stroke volume is increased. Dobutamine has little effect on mean arterial pressure in normotensive patients, but in patients who are hypotensive, because of low output, mean arterial pressure rises with the increase in cardiac output. Because dobutamine acts by stimulating cardiac beta
1-receptors, cyclic AMP in cardiac tissues is increased.

INDICATIONS
CARDIJECT 250 is indicated in adults who require parenteral inotropic support in the treatment of heart failure due to cardiomyopathies (primary disease and hypocontractile function of the cardiac muscle), myocardial infarction or cardiac surgical procedures.

CONTRA-INDICATIONS
Hypersensitivity to any of the ingredients.
CARDIJECT 250 should be avoided in patients with marked obstruction of cardiac ejection, such asidiopathic hypertrophic subaortic stenosis.
Safety during lactation and in children has not been established.

WARNINGS
CARDIJECT 250 acts primarily on beta
1-receptors and may produce hypertension, tachycardia, andectopic heart beats. Arrhythmias may be precipitated; it is claimed that dobutamine causes a lowerincidence of arrhythmias compared with isoprenaline and dopamine. If rapid ventricular rates occur inthe presence of obstructive coronary artery disease, ischemia can be induced and worsened.CARDIJECT 250 may cause a marked increase in heart rate or systolic blood pressure. Reduction ofdosage usually reverses these effects promptly.
Rapid ventricular rate response may occur in patients with atrial fibrillation since dobutaminefacilitates atrioventricular conduction. In patients who have atrial fibrillation with rapid ventricularresponse, a digitalis preparation should be used prior to institution of therapy with CARDIJECT 250.
If CARDIJECT 250 should cause serious ventricular arrhythmia, uncontrolled by lidocaine, its infusionshould be reduced or temporarily stopped. The infusion should be reduced or temporarily stopped if anundue rise in sinus rate or systolic blood pressure occurs.
CARDIJECT 250 should not be administered in the presence of uncorrected ventricular tachycardia orventricular fibrillation.
In patients with myocardial infarction, especially with widespread coronary artery disease, excessivedoses of dobutamine may intensify ischemia by increasing myocardial oxygen demands and causeanginal pain and ST-segment elevation.
In patients with asymmetric septal hypertrophy (idiopathic hypertrophic subaortic stenosis),administration of dobutamine may increase outlet obstruction as myocardial contractility improves (seeCONTRA-INDICATIONS).
Vasoconstriction has been observed, most notably in patients recently treated with beta-blocking agents.
Because the inotropic effect of CARDIJECT 250 stems from stimulation of cardiac beta
1-receptors, this effect is, of course, prevented by beta-blocking agents.

INTERACTIONS
CARDIJECT 250 has been found to be physically incompatible with the following products:furosemide, hydrocortisone sodium succinate, cefazolin, cefamandole naftate, cephalothin, penicillin,sodium bicarbonate, sodium ethacrynate and sodium heparin. Anaesthetics such as chloroform,halothane and other halogenated anaesthetics greatly sensitize the myocardium and may increase therisk of severe atrial and ventricular arrhythmias. CARDIJECT 250 should be used with caution and insubstantially reduced doses in patients receiving anaesthetics.
Simultaneous administration of CARDIJECT 250 with beta-adrenergic blocking agents may result inmutual inhibition of therapeutic effects; beta-blockade may antagonise the inotropic effects ofCARDIJECT 250 on the heart. CARDIJECT 250 may be ineffective or may have a slightvasoconstricting effect in patients who have recently received beta-blockers.
Concurrent use of tricyclic antidepressant or maprotiline may potentiate the cardiovascular and pressor effects, possibly resulting in arrhythmias, tachycardia, or severe hypertension or hyperpyrexia. Concurrent use of monoamine oxidase (MAO) inhibitors may prolong and intensify cardiac stimulation and vasopressor effects because of the release of catecholamines. This may result in cardiac arrhythmias or sudden and severe hypertensive and/or hyperpyretic crisis.

PREGNANCY AND LACTATION
Safety in pregnancy and lactation has not yet been established.

DOSAGE AND DIRECTIONS FOR USE
CARDIJECT 250 is intended for intravenous use only.
The usual intravenous infusion rate is 2,5 to 10 microgramsper kg of body weight per minute. The rate ofadministration and duration of therapy should be adjusted according to the patient’s response asdetermined by heart rate, blood pressure, cardiac output, and urine output. A range of 0,5 up to 40 micrograms per kg per minute has occasionally been required. When discontinuing therapy with CARDIJECT 250,it is advisable to decrease the dosage gradually.
Note: Do not add CARDIJECT 250 to 5% sodium bicarbonate injection or any other strongly alkaline solutions. CARDIJECT 250 should not be used in conjunction with other agents or diluents containing both sodium bisulphite and ethanol.
CARDIJECT 250 must be diluted with sterile water for injection or 5% dextrose injection to at least 50 mL prior to administration in the media listed below:
5% dextrose injection, 0,9% sodium chloride injection, ringers lactate injection or sodium lactateinjection.
Intravenous solution for administration should be used within 24 hours. Solutions containing CARDIJECT 250 may exhibit a colour, which, if present, will increase with time. This colour change is due to slight oxidation of agent, but there is no significant loss of potency during the time period stated above.
The following table is suggested as a guide to rates of delivery:
Rates of delivery of three different concentrations* of CARDIJECT 250 to achieve required dosage.
Required dosage
(micrograms/kg/min)
Rate of delivery (mL/kg/min) of the various concentrations of dobutamine
  250 micrograms/mL** 500 micrograms/mL*** 1000 micrograms/mL****
        0,5         0,002         0,001         0,0005
        1,0         0,004         0,002         0,001
        2,0         0,008         0,004         0,002
        4,0         0,016         0,008         0,004
        6,0         0,024         0,012         0,006
        8,0         0,032         0,016         0,008
        10,0         0,040         0,020         0,010
        12,0         0,048         0,024         0,012
        14,0         0,056         0,028         0,014

*Concentrations in excess of the highest presented here (1000 micrograms/mL) may be administered in patients whose fluid intake must be restricted. Concentrations of up to 5000 micrograms/mL have been given.
** One vial (250 mg) added to one litre of diluent.
*** Two vials (500 mg) added to one litre of diluent, or one vial (250 mg) added to 500 mL of diluent.
**** Four vials (1000 mg or 1 g) added to one litre of diluent, or one vial (250 mg) added to 250 mL of diluent.
The final volume administered should be determined by the fluid requirements of the patient.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side Effects
Since the half-life of dobutamine is only about 2 minutes most adverse effects can be corrected bydiscontinuing or reducing the rate of infusion.
Metabolism and nutritional disorders
Less frequent: Hypokalaemia.
Gastro-intestinal disorder
Frequent: Nausea and vomiting.
Nervous system disorders
Frequent: Headache.
Less frequent: Nervousness or restlessness, paraesthesia.
Cardiac disorders
Less frequent: Anginal pain, non-specific chest pain, palpitations or shortness of breath, tachycardia,hypertension, hypotension or ventricular arrhythmias.
A 10 mm to 20 mm rise in systolic blood pressure has been observed in most patients. Those with preexistinghypertension may exhibit an exaggerated pressor response. An increase in heart rate of 5 to 10 beats per minute may occur. In some instances patients have developed excessive tachycardia orectopic heart beats. CARDIJECT 250 may also increase the ventricular rate in patients with preexistingatrial fibrillation. Temporary discontinuation of the infusion or a reduction in dosage willusually reverse these conditions.
Musculoskeletal, connective tissue and bone disorders
Less frequent: Leg cramps.

Precautions
CARDIJECT 250 may exacerbate pre-existing tachycardia and hypertension; patients with atrialfibrillation should be given a cardiac glycoside before CARDIJECT 250 treatment to reduce the risk ofenhanced atrioventricular conduction leading to ventricular fibrillation.
Hypovolaemia should be corrected with suitable volume expanders before patients receive CARDIJECT 250.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
In case of overdosage, as evidenced by excessive blood pressure alteration or tachycardia, reduce the rate of administration or temporarily discontinue CARDIJECT 250 until the patient’s condition stabilises. Treatment is symptomatic and supportive.

IDENTIFICATION
CARDIJECT 250 is a white to off white lyophilized cake in 20 mLcolourless glass vial, with orangeflip-off tear down seal.
After reconstitution the solution is clear, colourless and free from any particulate matter or foreign particles.

PRESENTATION
CARDIJECT 250 is available in a 20 mL colourless Type 1 glass vial with a grey bromobutyl rubber stopper and a tear off, flip-off aluminium seal with orange colour.

STORAGE INSTRUCTIONS
Store below 25°C. Protect from light.
In combination with intravenous formulations it may be stored for 24 hours at 25°C.
Do not freeze.
KEEP OUT OF REACH OF CHILDREN.

REGISTRATION NUMBER
39/6.1/0609

NAME AND BUSINESS ADDRESS OF THE HOLDER OF THE CERTIFICATE OF REGISTRATION
Pharmaplan (Pty) Ltd
106 16th Road
Midrand

DATE OF PUBLICATION OF THE PACKAGE INSERT
7 April 2006

New addition to this site: December 2006
Source: Pharmaceutical Industry

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