SONOVUE 8mcl / ml powder+solvent for dispersion for injection medication leaflet

SonoVue 8 microlitres/mL powder and solvent for dispersion for injection

Each mL of the dispersion contains 8 µL sulphur hexafluoride microbubbles, equivalent to45 micrograms.

For the full list of excipients, see section 6.1

Powder and solvent for dispersion for injection.

White powder

Clear, colourless solvent

This medicinal product is for diagnostic use only.

SonoVue is for use with ultrasound imaging to enhance the echogenicity of the blood, or of fluids inthe urinary tract which results in an improved signal to noise ratio.

SonoVue should only be used in patients where study without contrast enhancement is inconclusive.

Echocardiography

SonoVue is a transpulmonary echocardiographic contrast agent for use in adult patients with suspectedor established cardiovascular disease to provide opacification of cardiac chambers and enhance leftventricular endocardial border delineation.

Doppler of macrovasculature

SonoVue increases the accuracy in detection or exclusion of abnormalities in cerebral arteries andextracranial carotid or peripheral arteries in adult patients by improving the Doppler signal to noiseratio.

SonoVue increases the quality of the Doppler flow image and the duration of clinically-useful signalenhancement in portal vein assessment in adult patients.

Doppler of microvasculature

SonoVue improves display of the vascularity of liver and breast lesions during Doppler sonography inadult patients leading to more specific lesion characterisation.

Ultrasonography of excretory urinary tract

SonoVue is indicated for use in ultrasonography of the excretory tract in paediatric patients fromnewborn to 18 years to detect vesicoureteral reflux. For the limitation in the interpretation of anegative urosonography, see section 4.4. and 5.1.

This product should only be used by physicians experienced in diagnostic ultrasound imaging.

Emergency equipment and personnel trained in its use must be readily available.

The recommended doses of SonoVue in adults are:

- B-mode imaging of cardiac chambers, at rest or with stress: 2 mL.

- Vascular Doppler imaging: 2.4 mL.

During a single examination, a second injection of the recommended dose can be made when deemednecessary by the physician.

Elderly Patients

The dose recommendations for intravenous administration also apply to elderly patients.

The safety and efficacy of SonoVue in patients under 18 years of age has not been established forintravenous administration and use in echocardiography and vascular Doppler imaging.

Intravesical use

- In paediatric patients the recommended dose of SonoVue is 1 mL

For instructions on reconstitution of the medicinal product before administration see section 6.6.

SonoVue should be administered immediately after drawing into the syringe by injection into aperipheral vein. Every injection should be followed by a flush with 5 mL of sodium chloride9 mg/mL (0.9%) solution for injection.

Intravesical use

After introduction of a sterile 6F-8F urinary catheter into the bladder under sterile conditions, thebladder is emptied of urine and then filled with saline (normal sterile 0.9% sodium chloride solution)to approximately one third or half of its predicted total volume [(age in years + 2) x 30] mL. SonoVueis then administered through the urinary catheter. Administration of SonoVue is followed bycompletion of bladder filling with saline until patient has the urge to micturate or there is the firstslight sign of back pressure to the infusion. Ultrasound imaging of the bladder and kidneys isperformed during filling and voiding of the bladder. Immediately following the first voiding, thebladder may be refilled with saline for a second cycle of voiding and imaging, without the need of asecond SonoVue administration. A low mechanical index (≤ 0.4) is recommended for imaging thebladder, ureters, and kidney during ultrasonography of the urinary tract with contrast.

Hypersensitivity to the active substance(s) or to any of the excipients listed in section 6.1.

Intravenous use of SonoVue is contraindicated in patients known to have right-to-left shunts, severepulmonary hypertension (pulmonary artery pressure >90 mmHg), uncontrolled systemic hypertension,and in patients with adult respiratory distress syndrome.

SonoVue must not be used in combination with dobutamine in patients with conditions suggestingcardiovascular instability where dobutamine is contraindicated.

Serious hypersensitivity reactions have been observed during or shortly following SonoVueadministration in patients with no prior exposure to sulphur hexafluoride microbubbles products,including patients with prior hypersensitivity reaction(s) to macrogol, also known as polyethyleneglycol (PEG) (see section 4.8).

SonoVue contains PEG (see section 6.1). There may be increased risk of serious reactions in patientswith prior hypersensitivity reaction(s) to PEG.

It is recommended to keep all patients under close medical supervision during and for at least30 minutes following the administration of SonoVue to monitor the risk of serious hypersensitivityreactions (see section 4.2).

Use caution when treating anaphylaxis with epinephrine in patients on beta blockers since responsemay be poor or promote undesired alpha-adrenergic and vagotonic effects (hypertension, bradycardia).

Patients with unstable cardiopulmonary status

ECG monitoring should be performed in high-risk patients as clinically indicated and a close medicalsupervision is recommended.

Use extreme caution when considering the administration of Sonvue in patients with recent acutecoronary syndrome or clinically unstable ischaemic cardiac disease, including: evolving or ongoingmyocardial infarction, typical angina at rest within last 7 days, significant worsening of cardiacsymptoms within last 7 days, recent coronary artery intervention or other factors suggesting clinicalinstability (for example, recent deterioration of ECG, laboratory or clinical findings), acute cardiacfailure, Class III/IV cardiac failure, or severe rhythm disorders because in these patients allergy likeand/or vasodilatory reactions may lead to life threatening conditions. SonoVue should only beadministered to such patients after careful risk/benefit assessment and a closely monitoring of vitalsigns should be performed during and after administration.

It should be emphasised that stress echocardiography not only can induce an ischaemic episode butalso the stressors may induce predictable, dose-dependent effects on the cardiovascular system (e.g.,increase in heart rate, blood pressure and ventricular ectopic activity for dobutamine, or decrease inblood pressure for adenosine and dipyridamole) as well as unpredictable, hypersensitivity reactions.

Therefore, if SonoVue is to be used in conjunction with stress echocardiography patients must have astable condition verified by absence of chest pain or ECG modification during the two preceding days.

Moreover, ECG and blood pressure monitoring should be performed during SonoVue-enhancedechocardiography with a pharmacological stress (e.g. with dobutamine).

Other concomitant diseases

Caution is advisable when administering the product to patients with: acute endocarditis, prostheticvalves, acute systemic inflammation and/or sepsis, hyperactive coagulation states and/or recentthromboembolism, and end-stage renal or hepatic disease, as the numbers of patients with thoseconditions who were exposed to SonoVue in the clinical trials were limited.

Interpretation of voiding urosonography with SonoVue and limitations of use

False negative cases can occur with voiding ultrasonography with SonoVue and have not beenclarified (see section 5.1).

Technical recommendation

In animal studies, the application of echo-contrast agents revealed biological adverse reactions(e.g. endothelial cell injury, capillary rupture) by interaction with the ultrasound beam. Although thesebiological side effects have not been reported in humans, the use of a low mechanical index isrecommended.

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially‘sodium-free’.

No interaction studies have been performed.

No clinical data on exposed pregnancies are available. Animal studies do not indicate harmful effectswith respect to pregnancy, embryonal/foetal development, parturition or postnatal development (seesection 5.3 Preclinical safety data). As a precautionary measure, it is preferable to avoid the use of

SonoVue during pregnancy.

It is not known if sulphur hexafluoride is excreted in human milk. However, based on its rapidelimination from the body via the expired air, it is considered that the breastfeeding can be resumedtwo to three hours after administration of SonoVue.

No clinical data are available. Animal studies do not indicate harmful effects on fertility.

SonoVue has no or negligible influence on the ability to drive and use machines.

Adult population-Intravenous use

The safety of SonoVue after intravenous administration was evaluated in 4653 adult patients whoparticipated in 58 clinical trials. The undesirable effects reported with SonoVue after intravenousadministration were, in general, non-serious, transient and resolved spontaneously without residualeffects. In clinical trials, the most commonly reported adverse reactions after intravenousadministration are: headache, injection site reaction, and nausea.

The adverse reactions are classified by System Organ Class and frequency, using the followingconvention: Very common (≥ 1/10), Common (≥ 1/100 to < 1/10), Uncommon (≥ 1/1,000 to < /100),

Rare (≥ 1/10,000 to < 1/1,000), Very rare (< 1/10,000), not known (cannot be estimated from theavailable data)

System Organ Class Adverse Drug Reactions

Frequency Category

Uncommon Rare Not known(≥ 1/1,000 to < 1/100) (≥ 1/10,000 to < 1/1000) Cannot be estimatedfrom available data

Immune system Hypersensitivity*disorders

Nervous system Headache, paraesthesia, Vasovagal reactiondisorders dizziness, dysgeusia

Eye disorders Vision blurred,

Cardiac disorders Myocardial infarction**

Myocardial ischemia**

Kounis syndrome***

Vascular disorders Flushing Hypotension

Gastrointestinal Nausea, Abdominal pain Vomitingdisorders

Skin and subcutaneous Rash Pruritustissue disorders

Musculoskeletal, Back painconnective tissue andbone disorders

General disorders and Chest discomfort, Chest pain, pain, fatigueadministration site injection site reaction,conditions feeling hot

* Cases suggestive of hypersensitivity may include: skin erythema, bradycardia, hypotension,dyspnoea, loss of consciousness, cardiac/cardio-respiratory arrest, anaphylactic reaction,anaphylactic shock.

** In some of the cases of hypersensitivity, in patients with underlying coronary artery disease,myocardial ischemia and/or myocardial infarctions were also reported.

***Allergic acute coronary syndrome

In very rare cases, fatal outcomes have been reported in temporal association with the use of SonoVue.

In all these patients there was a high underlying risk for major cardiac complications, which couldhave led to the fatal outcome.

Paediatric population-Intravesical use

The safety of SonoVue after intravesical administration was based on evaluation of publishedliterature involving use of SonoVue in over 6000 paediatric patients (age range 2 days to 18 years). Noadverse reactions were reported.

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

Since there have been no cases of overdose reported to date, neither signs nor symptoms of overdosehave been identified. In a Phase I study doses up to 52 mL of SonoVue were administered to normalvolunteers without serious adverse events being reported. In the event of overdose occurring, thepatient should be observed and treated symptomatically.

Pharmacotherapeutic group: Ultrasound contrast media

ATC code: VO8DA05.

Sulphur hexafluoride is an inert, innocuous gas, poorly soluble in aqueous solutions. There areliterature reports of the use of the gas in the study of respiratory physiology and in pneumaticretinopexy. The addition of sodium chloride 9 mg/mL (0.9%) solution for injection to the lyophilisedpowder followed by vigorous shaking results in the production of the microbubbles of sulphurhexafluoride. The microbubbles have a mean diameter of about 2.5 µm, with 90% having a diameterless than 6 µm and 99% having a diameter less than 11 µm. Each millilitre of SonoVue contains 8 µLof the microbubbles. The intensity of the reflected signal is dependent on concentration of themicrobubbles and frequency of the ultrasound beam. The interface between the sulphur hexafluoridebubble and the aqueous medium acts as a reflector of the ultrasound beam thus enhancing bloodechogenicity and increasing contrast between the blood and the surrounding tissues.

At the proposed clinical doses for intravenous administration, SonoVue has been shown to providemarked increase in signal intensity of more than 2 minutes for B-mode imaging in echocardiographyand of 3 to 8 minutes for Doppler imaging of the macrovasculature and microvasculature.

Intravesical use

For ultrasonography of the excretory urinary tract in paediatric patients, after intravesicaladministration, SonoVue increases the signal intensity of fluids within the urethra, bladder, ureters,and renal pelvis, and facilitates the detection of reflux of fluid from the bladder into the ureters.

The efficacy of SonoVue for detection/exclusion of vesicoureteral reflux was studied in two publishedopen label single centre studies. The presence or absence of vesicoureteral reflux with SonoVueultrasound was compared to the radiographic reference standard. In one study including 183 patients(366 kidney-ureter units), SonoVue ultrasound was correctly positive in 89 out 103 units with refluxand correctly negative in 226 out of 263 units without reflux. In the second study including228 patients (463 kidney-ureter units), SonoVue ultrasound was correctly positive in 57 out of 71 unitswith reflux and correctly negative in 302 out of 392 units without reflux.

The total amount of sulphur hexafluoride administered in a clinical dose is extremely small, (in a 2 mLdose the microbubbles contain 16 µl of gas). The sulphur hexafluoride dissolves in the blood and issubsequently exhaled.

After a single intravenous injection of 0.03 or 0.3 mL of SonoVue/kg (approximately 1 and 10 timesthe maximum clinical dose) to human volunteers, the sulphur hexafluoride was cleared rapidly. Themean terminal half-life was 12 minutes (range 2 to 33 minutes). More than 80% of the administeredsulphur hexafluoride was recovered in exhaled air within 2 minutes after injection and almost 100%after 15 minutes.

In patients with diffuse interstitial pulmonary fibrosis, the percent of dose recovered in expired airaveraged 100% and the terminal half-life was similar to that measured in healthy volunteers.

Non-clinical data reveal no special hazard for humans based on conventional studies of safetypharmacology, genotoxicity and toxicity to reproduction. Caecal lesions observed in some repeat-dosestudies with rats, but not in monkeys, are not relevant for humans under normal conditions ofadministration.

Intravesical local tolerance for SonoVue was also assessed. A single-dose study and a repeat-dosestudy, both followed by a treatment-free period, were performed in female rats with local toxicityevaluated through macroscopic and histopathological examination of both kidneys, ureters, the urinarybladder and urethra. It did not reveal any test item-related lesions in any of the examined organs, inparticular in the urinary bladder, in both the single-dose and the repeat-dose studies. It was thereforeconcluded that SonoVue is well tolerated in the urinary tract in the rat.

Macrogol 4000

Distearoylphosphatidylcholine

Dipalmitoylphosphatidylglycerol Sodium

Palmitic acid

Sodium chloride 9 mg/mL (0.9%) solution for injection.

This medicinal product must not be mixed with other medicinal products except those mentioned insection 6.6.

2 years.

Once reconstituted, chemical and physical stability has been demonstrated for 6 hours. From amicrobiological point of view, the medicinal product should be used immediately. If not usedimmediately, in use storage times and conditions prior to use are the responsibility of the user.

The medicinal product does not require any special storage conditions.

For storage conditions after reconstitution of the medicinal product, see section 6.3.

Type I colourless glass vial containing 25 mg of dry, lyophilised powder in an atmosphere of sulphurhexafluoride closed with a grey butyl rubber stopper and sealed with an aluminium crimp seal with aflip-off disc. A transfer system (MiniSpike).

Type I clear glass pre-filled syringe containing 5 mL sodium chloride 9 mg/mL (0.9%) solution forinjection.

Before use examine the product to ensure that the container and closure have not been damaged.

SonoVue must be prepared before use by injecting through the septum 5 mL of sodium chloride9 mg/mL (0.9%) solution for injection to the contents of the vial. The vial is then shaken vigorouslyfor twenty seconds after which the desired volume of the dispersion can be drawn into a syringe asfollows:

1 2 34 56 7 8v1.0-08/2000 ©BRG 20001. Connect the plunger rod by screwing it clockwise into the syringe.2. Open the MiniSpike transfer system blister and remove syringe tip cap.3. Open the transfer system cap and connect the syringe to the transfer system by screwing it inclockwise.4. Remove the protective disk from the vial. Slide the vial into the transparent sleeve of thetransfer system and press firmly to lock the vial in place.5. Empty the contents of the syringe into the vial by pushing on the plunger rod.6. Shake vigorously for 20 seconds to mix all the contents in the vial to obtain a white milkyhomogeneous liquid.7. Invert the system and carefully withdraw SonoVue into the syringe.8. Unscrew the syringe from the transfer system.

Do not use if the liquid obtained is clear and/or if solid parts of the lyophilisate are seen in thesuspension.

SonoVue should be administered immediately by injection into a peripheral vein for use inechocardiography and in vascular Doppler imaging in adults or by intravesical administration for usein ultrasonography of the excretory urinary tract in paediatric patients.

If SonoVue is not used immediately after reconstitution the microbubble dispersion should be shakenagain before being drawn up into a syringe. Chemical and physical stability of the microbubbledispersion has been demonstrated for 6 hours.

The vial is for a single use only.

Any unused medicinal product or waste material should be disposed of in accordance with localrequirements.

Bracco International B.V.

Argonstraat 36422 PH Heerlen

The Netherlands

EU/1/01/177/002

Date of first authorisation: 26 March 2001

Date of latest renewal: 24 April 2006

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.