Levovist (Galactose – Palmitic Acid)


Berlex Canada

Galactose – Palmitic Acid

Ultrasound Contrast Agent

Action And Clinical Pharmacology: Levovist is an ultrasound contrast agent consisting of granules which are composed of 99.9% galactose and 0.1% palmitic acid. Prior to use, Levovist must be reconstituted with sterilized water for injections and shaken vigorously by hand for 5 to 10 seconds. After injection of the suspension into a peripheral vein, Levovist leads to temporarily enhanced ultrasound echoes from the heart chambers and blood vessels. The distinct amplification of the ultrasound echo is caused primarily by micron-sized air bubbles, which are formed after suspension of the granules in water. Mediated by the palmitic acid additive, they remain stable for several minutes while in transit through the lungs and heart, and subsequent vascular bed before dissolving in the blood stream.

The pharmacokinetic investigation of Levovist was performed with the concentration of 400 mg/mL and injection volumes of 35 and 70 mL.

Galactose and palmitic acid are physiological substances with rapid metabolism.

After i.v. administration of Levovist, the galactose microparticles quickly dissolve in the blood stream. Galactose is rapidly distributed to the extracellular space and extracted by the liver. In the liver cells, galactose is converted to galactose-1-phosphate, then to glucose-1-phosphate, and glucose-6-phosphate which can enter the various pathways of glucose metabolism. Galactose is excreted via the kidneys if the plasma galactose level exceeds 50 mg/100 mL.

Palmitic acid is one of the most common fatty acids present in the human body. This 16-carbon atom and fully saturated fatty acid is one of the major constituents of the fats in the blood. Being highly miscible with the membranes of the cells, it immediately diffuses into the fat cells where it follows the usual metabolic process.

The plasma half-lives of galactose and palmitic acid, in adults, are in the range of 10 to 15 minutes and 1 to 4 minutes, respectively.

Depending on hepatic function, a prolonged elimination half-life can be expected. The elimination rate may therefore be reduced in cases of liver dysfunction and in neonates. As ethanol decreases the rate of galactose conversion in the liver, it may also prolong the half-life.

Results from clinical trials with Levovist show that within the range of recommended dosages (from 10 mL of 200 mg/mL, up to 8 mL of 400 mg/mL), Levovist produces no clinically relevant effects on physiological functions. Transient hemodynamic effects were observed at doses of 70 mL of the 400 mg/mL concentration injected as a bolus, which is more than 8-fold greater than the maximum recommended diagnostic dose.

Indications And Clinical Uses: One- and two-dimensional Doppler sonographic blood flow imaging in patients with insufficient Doppler signal intensity. B-mode contrast echocardiography.

Contra-Indications: Levovist should not be administered to patients with galactosemia.

Manufacturers’ Warnings In Clinical States: In patients with severe cardiovascular insufficiency close to cardiac decompensation (i.e., NYHA stage IV), the total osmotic load caused by the Levovist injections must be considered carefully.

Levovist must be prepared according to instructions (see Dosage) in order to ensure safe administration of the product. Precautions

Precautions: Pregnancy: The safe use of Levovist during pregnancy has not been established. Therefore, it should not be used unless the benefits outweigh the risks.

Children: The safety and effectiveness of Levovist in children have not been established.

Drug Interactions: The interaction of Levovist with other compounds has not been investigated.

Adverse Reactions: The safety of Levovist was evaluated in 1 819 patients during clinical trials for Doppler sonography and B-mode echocardiography. No serious adverse events were reported during the clinical trials. Most adverse events experienced by patients were transient, and graded as mild or moderate in severity. The most frequently reported adverse events were: vasodilatation [sensation of warmth] (6.2%), injection site pain (3.9%), paresthesia (3.9%) and pain (1.4%).

Injection Site: injection site reaction and inflammation. Slight local intolerance reactions after an accidental paravenous administration of Levovist might occur. In this case, symptomatic treatment is recommended (e.g., immobilisation, cold compresses and observation).

CNS: dizziness, headache, asthenia, chills and convulsion.

Body as a Whole: body odor.

Special Senses: taste perversion and abnormal vision.

Respiratory: dyspnea, increased cough, lung edema and hyperventilation.

Digestive: nausea, vomiting and dry mouth.

Skin and Appendages: pruritus and rash.

Musculoskeletal: myalgia and dystonia.

Urogenital: urinary urgency.

Symptoms And Treatment Of Overdose: Symptoms and Treatment: The risk of accidental poisoning with Levovist is extremely low.

An overdose of Levovist should be treated by prompt initiation of symptomatic therapy. For symptoms of osmotic diuresis: monitor the serum electrolytes and intravascular volume, and correct when necessary. For symptoms of hypervolemia: i.v. administration of diuretics (e.g., furosemide).

Dosage And Administration: Amplification of the ultrasound echo is dependent on the concentration of the microparticle suspension and the volume injected. After having prepared the suspension by adding the appropriate amount of sterilized water for injections and shaking it vigorously by hand for 5 to 10 seconds, let the suspension stand for 2 minutes before withdrawing into a syringe. The use of excessive negative pressure when the suspension is drawn into the syringe is to be avoided. Care must be taken to remove any visible air bubbles before injection. Levovist should be injected into a large vein (e.g., antecubital vein). The following dosages are recommended.

The i.v. injection should be done continuously (approximately 1 to 2 mL/s) in order to have homogeneous enhancement effects in the Doppler recording. To ensure that the total dose of Levovist is systemically delivered, the injection should be followed by a 5 to 10 mL normal saline flush.

A repeat injection of Levovist may be necessary in special cases, e.g., in order to examine several sectional planes. To achieve a stronger effect or longer duration of enhancement, the dose may be increased, particularly by choosing a higher concentration. The duration of the increased signal strength is usually 1 to 2 minutes for Doppler echocardiographic examinations, and 2 to 4 minutes for Doppler vascular examinations.

Additional injections can be repeated at 5-minute intervals. The maximum recommended dose is 6 injections of the highest single dose.

The i.v. injection should be given as bolus. To ensure that the total dose of Levovist is systemically delivered, the injection should be followed by a 5 to 10 mL normal saline flush. This can improve the reproducibility of the quantitatively measurable contrast effects. To facilitate the injection of the saline solution without delay, the use of a 3-way connector is recommended.

Additional injections can be repeated at 5-minute intervals. The maximum recommended dose is 6 injections of the highest single dose.

Reconstituted Suspensions: Prior to use, Levovist is reconstituted with sterilized water for injection. The concentration of the microparticle suspension and thereby the degree of the contrast effect produced by the microbubbles can be adjusted to the respective clinical demand by adding different specific amounts of sterilized water for injections.

Special Instructions: Preparation of the Levovist Suspension: Withdraw the appropriate amount of sterilized water for injection using the syringe. Remove the plastic cap from the vial containing the granules without disturbing the flanged metal cap. Pierce the rubber stopper with the minispike. Attach the syringe to the minispike, and transfer the water into the vial of Levovist granules. Prepare the suspension by immediately shaking vigorously by hand for 5 to 10 seconds. Do not use shaking devices or an ultrasound bath. Let the suspension stand for 2 minutes before use. Withdraw the ready-for-use, homogeneous, milky Levovist suspension through the mini-spike into the syringe and administer within 10 minutes of preparation.

The granules and sterilized water for injections should be at room temperature before making the suspension. After reconstitution, drawing the suspension up too quickly and warming the vial by holding it in the hand for a prolonged period should be avoided. This is necessary to prevent a decrease of the microbubble concentration and the formation of larger air bubbles due to the degassing processes. It is recommended to perform the injection via a flexible indwelling cannula with an adequate gauge size (e.g., 19 to 20 G). As usual, care must be taken to remove any macroscopically visible air bubbles from the suspension before injection. Should a slight sedimentation of the microparticles occur during standing time, resuspend the preparation by gently rotating it immediately before injection. Any suspension not used at one examination session must be discarded.

Availability And Storage: Each g of granules contains: galactose 999 mg and palmitic acid 1 mg. Maximum osmolality at 37°C (solution): 200 mg/mL, žsl1 175 mOsm/kg; 300 mg/mL, žsl1 965 mOsm/kg; 400 mg/mL, žsl2 894 mOsm/kg. Effective osmolality at 25°C (filtrate): 200 mg/mL, žsl910 mOsm/kg; 300 mg/mL, žsl980 mOsm/kg; 400 mg/mL, žsl950 mOsm/kg. Viscosity at 25°C (ready-for-use suspension): 200 mg/mL, žsl1.4 mPa.s; 300 mg/mL, žsl3.6 mPa.s; 400 mg/mL, žsl8.0 mPa.s. Viscosity at 25°C (filtrate): 200 mg/mL, 1.4 mPa.s; 300 mg/mL, 1.4 mPa.s; 400 mg/mL, 1.4 mPa.s.

The reconstituted suspensions have a stability of approximately 15 minutes in the vial without any loss of echogenicity. Vials of 4 g, cartons of 1 vial of granules, one 19 mL ampul of sterilized water for injection, one 20 mL disposable syringe and 1 minispike. Store at room temperature (15 to 30°C). Protect from light.

LEVOVIST® Berlex Canada Galactose – Palmitic Acid Ultrasound Contrast Agent

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