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 Соновью 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.
Intravenous use of Соновью 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.
Соновью must not be used in combination with dobutamine in patients with conditions suggesting cardiovascular instability where dobutamine is contraindicated.
Adult population-Intravenous use
The safety of Соновью after intravenous administration was evaluated in 4653 adult patients who participated in 58 clinical trials. The undesirable effects reported with Соновью after intravenous administration were, in general, non-serious, transient and resolved spontaneously without residual effects. In clinical trials, the most commonly reported adverse reactions after intravenous administration are: headache, injection site reaction, and nausea.
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 < /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 (> 1/1,000 to < 1/100) | Rare (> 1/10,000 to < 1/1000) | Not known Cannot be estimated from available data | |
| Immune system disorders | Hypersensitivity* | ||
| Psychiatric disorders | Insomnia | ||
| Nervous system disorders | Headache, paraesthesia, dizziness, dysgeusia | Sinus headache | Vasovagal reaction |
| Eye disorders | Vision blurred, | ||
| Cardiac disorders | Myocardial infarction** Myocardial ischemia** | ||
| 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 discomfort, injection site reaction, feeling hot | Chest pain, pain, fatigue | |
| Investigations | Blood glucose increased | ||
* Cases suggestive of hypersensitivity may include: skin erythema, bradycardia, hypotension, dyspnoea, loss of consciousness, cardiac/cardio-respiratory arrest anaphylactic reaction, anaphylactoid reaction or 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.
In very rare cases, fatal outcomes have been reported in temporal association with the use of Соновью. In all these patients there was a high underlying risk for major cardiac complications, which could have led to the fatal outcome.
Paediatric population-Intravesical use
The safety of Соновью after intravesical administration was based on evaluation of published literature involving use of Соновью in over 6000 paediatric patients (age range 2 days to 18 years). No adverse reactions were reported.
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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.
Intravesical local tolerance for Соновью was also assessed. A single-dose study and a repeat-dose study, both followed by a treatment-free period, were performed in female rats with local toxicity evaluated through macroscopic and histopathological examination of both kidneys, ureters, the urinary bladder and urethra. It did not reveal any test item-related lesions in any of the examined organs, in particular in the urinary bladder, in both the single-dose and the repeat-dose studies. It was therefore concluded that Соновью is well tolerated in the urinary tract in the rat.
This medicinal product is for diagnostic use only.
Соновью is for use with ultrasound imaging to enhance the echogenicity of the blood, or of fluids in the urinary tract which results in an improved signal to noise ratio.
Соновью should only be used in patients where study without contrast enhancement is inconclusive.
Echocardiography
Соновью is a transpulmonary echocardiographic contrast agent for use in adult patients with suspected or established cardiovascular disease to provide opacification of cardiac chambers and enhance left ventricular endocardial border delineation.
Doppler of macrovasculature
Соновью increases the accuracy in detection or exclusion of abnormalities in cerebral arteries and extracranial carotid or peripheral arteries in adult patients by improving the Doppler signal to noise ratio.
Соновью increases the quality of the Doppler flow image and the duration of clinically-useful signal enhancement in portal vein assessment in adult patients.
Doppler of microvasculature
Соновью improves display of the vascularity of liver and breast lesions during Doppler sonography in adult patients leading to more specific lesion characterisation.
Ultrasonography of excretory urinary tract
Соновью is indicated for use in ultrasonography of the excretory tract in paediatric patients from newborn to 18 years to detect vesicoureteral reflux. and 5.1.
Pharmacotherapeutic group: Ultrasound contrast media
ATC code: VO8DA05.
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 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 µm, with 90% having a diameter less than 6 µm and 99% having a diameter less than 11 µm. Each millilitre of Соновью contains 8 µL of the microbubbles. The intensity of the reflected signal is dependent on concentration of the microbubbles and frequency of the ultrasound beam.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.
Intravenous use
At the proposed clinical doses for intravenous administration, Соновью 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.
Intravesical use
For ultrasonography of the excretory urinary tract in paediatric patients, after intravesical administration, Соновью 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 Соновью for detection/exclusion of vesicoureteral reflux was studied in two published open label single centre studies. The presence or absence of vesicoureteral reflux with Соновью ultrasound was compared to the radiographic reference standard. In one study including 183 patients (366 kidney-ureter units), Соновью ultrasound was correctly positive in 89 out 103 units with reflux and correctly negative in 226 out of 263 units without reflux. In the second study including 228 patients (463 kidney-ureter units), Соновью ultrasound was correctly positive in 57 out of 71 units with 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 mL dose the microbubbles contain 16 µl 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 Соновью/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.
Hypersensitivity reactions
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.
Intravenous use
Patients with unstable cardiopulmonary status
ECG monitoring should be performed in high-risk patients as clinically indicated. It is recommended to keep the patient under close medical supervision during and for at least 30 minutes following the administration of Соновью.
Use extreme caution when considering the administration of Sonvue 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 because in these patients allergy like and/or vasodilatory reactions may lead to life threatening conditions. Соновью should only be administered to such patients after careful risk/benefit assessment and a closely monitoring of vital signs should be performed during and after administration.
It should be emphasised that stress echocardiography, which can mimic an ischaemic episode, could potentially increase the risk of Соновью utilisation. Therefore, if Соновью 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 Соновью-enhanced echocardiography with a pharmacological stress (e.g. with dobutamine).
Chronic obstructive pulmonary disease
Caution is advised when Соновью is administered to patients with clinically significant pulmonary disease, including severe chronic obstructive pulmonary disease.
Other concomitant diseases
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, as the numbers of patients with those conditions who were exposed to Соновью in the clinical trials were limited.
Patients on mechanical ventilation or with unstable neurological diseases
Соновью is not suitable for use in ventilated patients, and those with unstable neurological diseases.
Interpretation of voiding urosonography with Соновью and limitations of use
False negative cases can occur with voiding ultrasonography with Соновью and have not been clarified.
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 these biological side effects have not been reported in humans, the use of a low mechanical index is recommended.
Excipients
This medicinal product contains less than 1 mmol sodium (23mg) per dose, i.e. essentially 'sodium-free'.
Соновью has no or negligible influence on the ability to drive and use machines.
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.
Posology
Intravenous use
The recommended doses of Соновью 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 deemed necessary by the physician.
Elderly Patients
The dose recommendations for intravenous administration also apply to elderly patients.
Paediatric Patients
The safety and efficacy of Соновью in patients under 18 years of age has not been established for intravenous administration and use in echocardiography and vascular Doppler imaging.
Intravesical use
- In paediatric patients the recommended dose of Соновью is 1mL
Method of administration
Intravenous use
Соновью 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.
Intravesical use
After introduction of a sterile 6F-8F urinary catheter into the bladder under sterile conditions, the bladder 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. Соновью is then administered through the urinary catheter. Administration of Соновью is followed by completion of bladder filling with saline until patient has the urge to micturate or there is the first slight sign of back pressure to the infusion. Ultrasound imaging of the bladder and kidneys is performed during filling and voiding of the bladder. Immediately following the first voiding, the bladder may be refilled with saline for a second cycle of voiding and imaging, without the need of a second Соновью administration. A low mechanical index (≤ 0.4) is recommended for imaging the bladder, ureters, and kidney during ultrasonography of the urinary tract with contrast.
Before use examine the product to ensure that the container and closure have not been damaged.
Соновью 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:
1. 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 in clockwise.
4. 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.
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 milky homogeneous liquid.
7. Invert the system and carefully withdraw Соновью 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 the suspension.
Соновью should be administered immediately by injection into a peripheral vein for use in echocardiography and in vascular Doppler imaging in adults or by intravesical administration for use in ultrasonography of the excretory urinary tract in paediatric patients.
If Соновью 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 use only.
Any unused medicinal product or waste material should be disposed of in accordance with local requirements.
