SonoVue 8 microlitres / ml powder and solvent for dispersion for injection
One ml contains 8 ul of sulphur hexafluoride microbubbles On reconstitution as directed, 1 ml of the resulting dispersion contains 8 ul sulphur hexafluoride in the microbubbles, equivalent to 45 microgrammes. For a full list of excipients, see section 6.1
Powder and solvent for dispersion for injection. SonoVue is a kit including 1 vial containing 25 mg of lyophilised powder 1 pre-filled syringe containing 5 ml sodium chloride 1 Mini-Spike transfer system Information on the appearance of the reconstituted solution is given in section 6.6.
This medicinal product is for diagnostic use only. SonoVue is for use with ultrasound imaging to enhance the echogenicity of the blood, 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 patients with suspected or established cardiovascular disease to provide opacification of cardiac chambers and enhance left ventricular endocardial border delineation.
Doppler of macrovasculature
SonoVue increases the accuracy in detection or exclusion of abnormalities in cerebral arteries and extracranial carotid or peripheral arteries by improving the Doppler signal to noise ratio. SonoVue increases the quality of the Doppler flow image and the duration of clinically-useful signal enhancement in portal vein assessment.
Doppler of microvasculature
SonoVue improves display of the vascularity of liver and breast lesions during Doppler sonography, leading to more specific lesion characterisation.
This product should only be used by physicians experienced in diagnostic ultrasound imaging. The recommended doses of SonoVue 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 deemed necessary by the physician.
Elderly Patients
The dosage recommendations also apply to elderly patients.
Paediatric Patients
The safety and effectiveness of SonoVue in patients under 18 years old has not been established and the product should not be used in these patients. The microbubble dispersion is prepared before use by injecting through the septum 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection to the contents of the vial. The vial is then shaken vigorously for a few seconds until the lyophilisate is completely dissolved. The desired volume of the dispersion can be drawn into a syringe any time up to six hours after reconstitution. Just before drawing into the syringe, the vial should be agitated to re-suspend the microbubbles. SonoVue should be administered immediately after drawing into the syringe by injection into a peripheral vein. Every injection should be followed by a flush with 5 ml of sodium chloride 9 mg/ml (0.9%) solution for injection. For instructions for preparation see section 6.6.
SonoVue should not be administered to patients with known hypersensitivity to sulphur hexafluoride or to any of the components of SonoVue. SonoVue is contraindicated for use in patients with recent acute coronary syndrome or clinically unstable ischaemic cardiac disease, including: evolving or ongoing myocardial infarction, typical angina at rest within last 7 days, significant worsening of cardiac symptoms within last 7 days, recent coronary artery intervention or other factors suggesting clinical instability (for example, recent deterioration of ECG, laboratory or clinical findings), acute cardiac failure, Class III/IV cardiac failure, or severe rhythm disorders. SonoVue is contraindicated in patients known to have right-to-left shunts, severe pulmonary hypertension (pulmonary artery pressure >90 mmHg), uncontrolled systemic hypertension, and in patients with adult respiratory distress syndrome. The safety and efficacy of SonoVue have not been established in pregnant and lactating women therefore, SonoVue should not be administered during pregnancy and lactation (see Section 4.6).
ECG monitoring should be performed in high-risk patients as clinically indicated. It should be emphasised that stress echocardiography, which can mimic an ischaemic episode, could potentially increase the risk of SonoVue utilisation. Therefore, if SonoVue is to be used in conjunction with stress echocardiography patients must have a stable 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-enhanced echocardiography with a pharmacological stress (e.g. with dobutamine). Care should be taken in patients with ischaemic cardiac disease because in these patients allergy-like and/or vasodilatory reactions may lead to life-threatening conditions. Emergency equipment and personnel trained in its use must be readily available. In the event of an anaphylactic reaction, beta blockers (including eye drop preparations) may aggravate the reaction. Patients may be unresponsive to the usual doses of adrenaline used to treat the allergic reactions. Caution is advised when SonoVue is administered to patients with clinically significant pulmonary disease, including severe chronic obstructive pulmonary disease. It is recommended to keep the patient under close medical supervision during and for at least 30 minutes following the administration of SonoVue. Numbers of patients with the following conditions who were exposed to SonoVue in the clinical trials were limited, and therefore, caution is advisable when administering the product to patients with: acute endocarditis, prosthetic valves, acute systemic inflammation and/or sepsis, hyperactive coagulation states and/or recent thromboembolism, and end-stage renal or hepatic disease. SonoVue is not suitable for use in ventilated patients, and those with unstable neurological diseases. In animal studies, the application of echo-contrast agents revealed biological side effects (e.g. endothelial cell injury, capillary rupture) by interaction with the ultrasound beam. Although these biological side effects have not been reported in humans, the use of a low mechanical index is recommended.
No specific interaction studies have been performed. There was no apparent relationship with respect to occurrence of adverse events in the clinical studies for patients receiving various categories of the most common concomitant medications.
No clinical data on exposed pregnancies are available. Animal studies do not indicate harmful effects with respect to pregnancy, embryonal/foetal development, parturition or postnatal development (see section 5.3 Preclinical safety data). Caution should be exercised when prescribing to pregnant women. It is not known if sulphur hexafluoride is excreted in human milk. Therefore, caution should be exercised when SonoVue is administered to breast-feeding women.
On the basis of the pharmacokinetic and pharmacodynamic profiles, no or negligible influence is expected with the use of SonoVue on the ability to drive or use machines.
The safety of SonoVue was evaluated in 4653 adult patients who participated in 58 clinical trials.. The adverse reactions are classified by System Organ Class and frequency, using the following convention: Very common (>= 1/10), Common (>= 1/100 to < 1/10), Uncommon (>= 1/1,000 to < 1/100), Rare (>= 1/10,000 to < 1/1,000), Very rare (< 1/10,000), not known (cannot be estimated from the available data)
| System Organ Class | Adverse Drug Reactions | ||
| Frequency Category | |||
| Uncommon (>=1/1,000to <1/100) | Rare (>=1/10,000to<1/1000) | Not known Cannot be estimated from available data | |
| Immune system disorders | Hypersensitivity, anaphylactic reaction, anaphylactoid reaction | ||
| Psychiatric disorders | Insomnia | ||
| Nervous system disorders | Headache, paraesthesia, dizziness, dysgeusia | Sinus headache | Loss of consciousness, Vasovagal reaction |
| Eye disorders | Vision blurred, | ||
| Vascular disorders | Flushing | Hypotension | |
| Respiratory, thoracic and mediastinal disorders | Pharyngitis | ||
| Gastrointestinal disorders | Nausea | Abdominal pain | |
| Skin and subcutaneous tissue disorders | Pruritus, rash | ||
| Musculoskeletal, connective tissue and bone disorders | Back pain | ||
| General disorders and administration site conditions | Chest pain, chest discomfort, pain, fatigue, injection site reaction, feeling hot | ||
| Investigations | Blood glucose increased | ||
In some of the cases of hypersensitivity, in patients with underlying coronary artery disease, myocardial ischemia and/or myocardial infarctions were also reported. 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 could have led to the fatal outcome.
Since there have been no cases of overdose reported to date, neither signs nor symptoms of overdose have been identified. In a Phase I study doses up to 56 ml of SonoVue were administered to normal volunteers without serious adverse events being reported. In the event of overdose occurring, the patient should be observed and treated symptomatically.
Pharmacotherapeutic group: Ultrasound contrast media ATC code: VO8DA. The addition of sodium chloride 9 mg/ml (0.9%) solution for injection to the lyophilised powder followed by vigorous shaking results in the production of the microbubbles of sulphur hexafluoride. The microbubbles have a mean diameter of about 2.5 um, with 90% having a diameter less than 6 um and 99% having a diameter less than 11 um. Each millilitre of SonoVue contains 8 ul of the microbubbles. The interface between the sulphur hexafluoride bubble and the aqueous medium acts as a reflector of the ultrasound beam thus enhancing blood echogenicity and increasing contrast between the blood and the surrounding tissues. The intensity of the reflected signal is dependent on concentration of the microbubbles and frequency of the ultrasound beam. At the proposed clinical doses, SonoVue has been shown to provide marked increase in signal intensity of more than 2 minutes for B-mode imaging in echocardiography and of 3 to 8 minutes for Doppler imaging of the macrovasculature and microvasculature. Sulphur hexafluoride is an inert, innocuous gas, poorly soluble in aqueous solutions. There are literature reports of the use of the gas in the study of respiratory physiology and in pneumatic retinopexy.
The total amount of sulphur hexafluoride administered in a clinical dose is extremely small, (in a 2 ml dose the microbubbles contain 16 ul of gas). The sulphur hexafluoride dissolves in the blood and is subsequently exhaled. After a single intravenous injection of 0.03 or 0.3 ml of SonoVue/kg (approximately 1 and 10 times the maximum clinical dose) to human volunteers, the sulphur hexafluoride was cleared rapidly. The mean terminal half-life was 12 minutes (range 2 to 33 minutes). More than 80% of the administered sulphur 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 air averaged 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 safety pharmacology, genotoxicity and toxicity to reproduction. Caecal lesions observed in some repeat-dose studies with rats, but not in monkeys, are not relevant for humans under normal conditions of administration.
Powder:
Macrogol 4000
Distearoylphosphatidylcholine Dipalmitoylphosphatidylglycerol Sodium Palmitic acid
Solvent:
Sodium chloride 9 mg/ml (0.9%) solution for injection
In the absence of compatibility studies, SonoVue should not be admixed with any other medicinal product except the solvent provided.
2 years. Once reconstituted, chemical and physical stability has been demonstrated for 6 hours. From a microbiological point of view, the product should be used immediately. If not used immediately, 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 of the reconstituted medicinal product, see section 6.3.
Presentation 02 (with separate MiniSpike transfer system): 25 mg of dry, lyophilised powder in an atmosphere of sulphur hexafluoride in a colourless Type I glass vial, with elastomeric closure. Separate transfer system. Type I glass pre-filled syringe containing 5 ml sodium chloride 9 mg/ml (0.9%) solution for injection.
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 chloride 9 mg/ml (0.9%) solution for injection to the contents of the vial. The vial is then shaken vigorously for twenty seconds after which the desired volume of the dispersion can be drawn into a syringe as follows: Presentation 02 (with separate MiniSpike transfer system)
1 2 3
4 5
6 7 8
v1.0-08/2000 (c)BRG 2000
Connect the plunger rod by screwing it clockwise into the syringe.
Open the MiniSpike transfer system blister and remove syringe tip cap.
Open the transfer system cap and connect the syringe to the transfer system by screwing it in clockwise.
Remove the protective disk from the vial. Slide the vial into the transparent sleeve of the
transfer system and press firmly to lock the vial in place. Empty the contents of the syringe into the vial by pushing on the plunger rod. Shake vigorously for 20 seconds to mix all the contents in the vial to obtain a white milky homogeneous liquid. Invert the system and carefully withdraw SonoVue into the syringe. Unscrew the syringe from the transfer system.
SonoVue should be administered immediately by injection into a peripheral vein. If SonoVue is not used immediately after reconstitution the microbubble dispersion should be shaken again before being drawn up into a syringe. Chemical and physical stability of the microbubble dispersion has been demonstrated for 6 hours. The vial is for a single examination only. Any unused dispersion remaining at the end of an examination or waste material must be discarded in accordance with local requirements.
Bracco International B.V. Strawinskylaan 3051 NL - 1077 ZX Amsterdam The Netherlands
EU/1/01/177/002
26 March 2001 / 24 April 2006
Name and address of the manufacturer responsible for batch release
Bracco Imaging S.p.A. Via Ribes 5, Biondustry Park Colleretto Giacosa - 10010 (TO) Italy
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product Characteristics, section 4.2)
Not applicable.
Pharmacovigilance system The MAH must ensure that the system of pharmacovigilance in Module 1.8.1. of the Marketing Authorisation is in place and functioning before and whilst the product is on the market. Risk Management Plan The MAH commits to performing the studies and additional pharmacovigilance activities detailed in the Pharmacovigilance Plan, as agreed in version 1 of the Risk Management Plan (RMP) presented in Module 1.8.2. of the Marketing Authorisation and any subsequent updates of the RMP agreed by the CHMP. As per the CHMP Guideline on Risk Management Systems for medicinal products for human use, any updated RMP should be submitted at the same time as t he following Periodic Safety Update Report (PSUR). In addition, an updated RMP should be submitted: When new information is received that may impact on the current Safety Specification, Pharmacovigilance Plan or risk minimisation activities Within 60 days of an important (pharmacovigilance or risk minimisation) milestone being reached At the request of the European Medicines Agency PSURs: The MAH will provide a PSUR covering the period 01/10/2005 to 30/09/2006 and continue with yearly PSURs unless otherwise agreed with CHMP.