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Logo ECHOVIST-200

SCHEDULING STATUS:
S1

PROPRIETARY NAME
(and dosage form):

ECHOVIST-200
Microcrystalline suspension for intravenous and transcervical administration

COMPOSITION
1 g granules contains
galactose microparticles 1 g.
1 mL aqueous solution for production of the suspension contains galactose 200 mg.
3 g granules plus 13,5 mL of aqueous solution gives 15 mL ready-to-use suspension.

Echovist-200 concentration 200 mg galactose microparticles/mL suspension
Total concentration of the galactose (w/v)
(particles and solution)
        38%
"Effective" osmolality of the freshly produced
suspension (37°C; mosm/kg H2O)
        1699
Viscosity of the freshly produced suspension
(25°C; mPa.s or cP)
        4,00

PHARMACOLOGICAL CLASSIFICATION
A. 28 Contrast media.

PHARMACOLOGICAL ACTION
Echovist-200 is a new type of contrast medium for ultrasound examinations. It consists of a suspension of soluble galactose microparticles (99% <12 microm., 95% <8 microm.) in aqueous 20% (w/v) galactose solution. After intravenous injection, this microbubble-microparticle suspension leads to a marked increase of the echo signals from the venous vascular bed and the blood-filled spaces of the right heart as a result of the acoustically active inhomogeneities produced.
Echovist-200 makes it possible to observe the blood flow in the echogram/Doppler image or in the M-mode or Doppler recording and is therefore suitable for the diagnosis of all haemodynamically active organic defects of the right heart or in the venous circulation.
Because of the short intravascular life of the microparticles and microbubbles, transit through the pulmonary circulation is, as a rule, unusual. Consequently, the observation of the contrast effects in the left heart chamber is usually an indication of the pathological condition of transseptal or intrapulmonary shunt flow.
In individual cases, however, the use of transoesophageal transducers has resulted in the detection of faint contrast effects in the left heart chamber of patients in whom no shunt flow was demonstrable. In contrast to shunt flow, however, these contrast effects are not observed immediately on influx of the contrast agent into the right ventricle, but only after the agent has passed through the pulmonary circulation (after at least 4-5 heart actions).
The galactose and the small amount of air in the bubbles are completely absorbed after transcervical administration.
Pharmacokinetics
After intravascular mixing of the suspension with blood plasma, the galactose microparticles and bubbles of air are quickly dissolved as a result of the concentration gradient. No passage through the capillary bed of the lungs is therefore likely. The galactose first of all becomes dispersed in the extracellular space and is subjected to glucose metabolism independent of insulin. Galactose is stored above all in the liver through the formation of galactose-1-phosphate, or is metabolised and broken down to CO2 after isomerisation to glucose-1-phosphate. If the plasma galactose level exceeds about 50 mg/100 mL and, therefore, the elimination rate of the liver, galactose is eliminated via the kidneys. The elimination rate in patients with liver disease is about one third lower than in healthy subjects, in whom the plasma galactose level falls by 10% per minute. Total clearance is about 40% lower in patients with liver disease. In the case of liver damage up to 60% of the amount of galactose administered is eliminated via the kidneys, while about 40% is utilised extrahepatically.
Galactose has a half-life of about 10-11 minutes in adults and of about 7-9 minutes in children.
Elimination may be substantially prolonged after consumption of alcohol.

INDICATIONS
Doppler-echocardiographic examinations for the detection, exclusion or follow-up of pathological states leading to haemodynamic changes in particular : defects of the tricuspid and pulmonary valves, congenital defects (eg atrial septum defects, ventricular septum defects), intracavitary masses and thrombi, and involvement of the right heart in other pathological processes.
Ultrasound examinations of the female genital tract, in particular for the demonstration or exclusion of acquired or congenital changes of the uterine cavity and for the visualisation of the Fallopian tubes and investigation of their patency ("hysterosalpingo-contrast sonography").

CONTRA-INDICATIONS
Galactosaemia.
In the case of transcervical administration, in addition:
Inflammatory processes of the female genital tract.
Intact pregnancy.
Insufficient data are available to recommend use in patients under 18 years of age.

DOSAGE AND DIRECTIONS FOR USE
For preparation of the ready-to-use Echovist-200 suspension (see diagrams).
The galactose solution (13,5 mL) is drawn up into a syringe and then transferred to the vial containing 3 g granules using the mandrel supplied. The granules are then suspended in the galactose solution by immediate vigorous shaking for about 5 seconds. The resulting homogenous milky-white suspension should be injected within the next five minutes in order to obtain consistently well reproducible contrast effects.
Note : Any galactose microparticles adhering to the inner walls of the vial are taken up during the preparation of the ready-to-use suspension.
The granules and the galactose solution should be at room temperature when suspension takes place. Warming the suspension (eg by holding it in the hands for a prolonged period) and the induction of excessive negative pressure (eg on drawing the suspension up) should be avoided wherever possible so as not to cause a decrease of the microbubble concentration or the development of larger bubbles of air as a result of degassing processes in the carrier solution. The mandrel is used again for withdrawal of the suspension. After the suspension has been drawn up into the syringe and before it is injected, care must be taken that all macroscopically recognisable bubbles of air are removed.
The ready-to-use solution has to be prepared according to instructions.
Any suspension not used at one examination session must be discarded.

Intravenous administration
It is always advisable to give the Echovist-200 injections via a flexible venous indwelling cannula of sufficiently large calibre. The use of Luer-LoK connections is also a practical advantage.
If desired (eg for quantitative evaluations), the bolus dynamics and, therefore, the reproducibility of the quantitatively measurable contrast effect can be increased by an immediate after-injection of about 5-10 mL physiological saline solution. The use of a three-way tap open to all sides is recommended so that the saline solution can be injected without delay.
O Doppler echocardiography
The following dosages are recommended for all Doppler-echocardiographic indications for the demonstration of the right heart chambers:
  Volumes of suspension per injection : 4-10 mL
  Recommended maximum dose: 5 injections of the maximum single dose
In general, the intravenous administration of 4 mL per image setting is sufficient. Depending on the question, this amount should be given either as a bolus or as a smooth injection.
The dose can be adapted to individual sound-conducting or haemodynamic situations by increasing the injection volume up to a maximum of 10 mL per injection. Experience shows that any increases should be made in steps of 2 mL and that the next injection of Echovist-200 should not be given until the contrast effect recognisable in the image has worn off.
The injection of only 1 mL or 2 mL may be diagnostically adequate in individual cases in which the patient's sound conductivity is particularly good or in cases of pronounced tricuspid insufficiency with a large volume of regurgitating blood or reduced pump function.

Transcervical administration
The reusable instruments normally employed for administering X-ray contrast media can be used for the transcervical administration of Echovist-200. However, the use of an intrauterine balloon catheter is to be recommended.
O Hysterosalpingo-contrast sonography
2-5 mL suspension is usually sufficient for the demonstration of the uterine cavity.
The additional intermittent administration of doses of 1-2 mL under sonographic control up to a total dose of, in general, about 15 mL is sufficient to demonstrate the Fallopian tubes and to check their patency.

SIDE EFFECTS AND SPECIAL PRECAUTIONS
Side effects
Intravenous administration
A transitory sensation of warmth or cold and of pain in the vicinity of the injection site or along the draining vein may occur during or shortly after the injection. Short-lasting tingling, a feeling of numbness, sensations of taste and dizziness have been reported.
Pain and tissue irritation may occur on paravascular injection.
No hypersensitivity reactions to the administration of galactose have so far been reported.
Transcervical administration
The distension of the uterine cavity and tubes caused by filling with the contrast agent can result in pain which is particularly pronounced in the presence of occluded tubes.
Vasovagal reactions, eg outbreaks of sweating, dizziness, nausea and vomiting, may occur.
The possibility of ascending genital infection owing to the method itself cannot be ruled out.

Special precautions
Intravenous administration
Because of the hyperosmolality of Echovist-200, the benefits must be weighed very carefully against the risk in severe cardiovascular insufficiency.
Minor additional contrast effects may occur in the right heart or in the veins in individual cases on rapid and sudden compression of the veins due to muscle movement, inflation of the sphygmomanometer cuff or a change of position by the patient after the preceding injection of the Echovist-200 suspension. These contrast effects are caused by portions of the suspension which, due to low flow rates have been separated virtually undiluted by blood in recesses of the venous flow, eg venous valves or at the vascular endothelium, during transit of the previous bolus. They then join the venous blood stream again as a result of the sudden increases in the flow rate, leading to the described delayed contrast effects (increases of echogenicity) in the right heart.
Depending on liver function and the dose injected, determinations of galactose may show elevated values for up to 24 hours after the examination.
Transcervical administration
To keep the risk of ascending genital infection inherent in the method as small as possible, aseptic conditions must be observed during use of Echovist-200 in hysterosalpingo-contrast sonography. Administer during the first half of the menstrual cycle.

KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT
Symptoms
In theory, the following findings are possible because of the hyperosmolality of the suspension : hypervolaemia and osmotic diuresis with electrolyte shifts and perhaps change of haematocrit.
Treatment
Osmotic diuresis : control of blood volume (haematocrit) and serum electrolyte and if necessary replacement.
Hypervolaemia : administration of diuretics (eg furosemide) in accordance with symptoms and signs.

IDENTIFICATION
White granulate and clear, colourless to faintly yellowish solution.

PRESENTATION
Combination pack consisting of:
1 vial of 20 mL with 3 g granulate
1 vial of 15 mL with 13,5 mL galactose solution
1 mandrel

STORAGE INSTRUCTIONS
Store below 30 C. Keep out of reach of children.

REGISTRATION NUMBER
28/28/0441

NAME AND BUSINESS ADDRESS OF THE APPLICANT
Schering (Pty) Ltd
(Reg No: 64/09072/07)
106 Sixteenth Road
Randjespark
Midrand 1685
P O Box 5278
Halfway House 1685

DATE OF PUBLICATION OF THIS PACKAGE INSERT
29.04.1996

{Production of the ready-to use Echovist-200 suspension illustrated here}

SCHERING (PTY) LTD
(Reg No: 64/09072/07)
Subsidiary of
Schering AG Germany

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