Only LUMASON® ultrasound enhancing agent has multiple indications for adult and pediatric patients.
Bracco’s perspective on recent publications reporting LUMASON® (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for intravenous use or intravesical use safety information
As a company dedicated to advancing the field of contrast-enhanced ultrasound (CEUS), Bracco takes any observations about the safe use of products like LUMASON® ultrasound enhancing agent (UEA) seriously. Our priority is to ensure that every Bracco product is safe and effective for patients and of the highest quality.
To support this commitment, Bracco maintains a robust, global system to constantly monitor the quality and safety of its products, collaborate with health authorities, and regularly provide integrated medical safety evaluations and benefit-risk assessments.
We read with great interest the recent publication by Ali et al. in the Journal of the American Society of Echocardiography (JASE) titled “Incidence of Severe Adverse Drug Reactions to Ultrasound Enhancement Agents in a Contemporary Echocardiography Practice,”2 which shortly followed another recent publication by Filippone et al. in Frontiers of Cardiovascular Medicine titled “Safety of LUMASON® (SonoVue®) in special populations and critically ill patients”.3
Study by Ali et al., JASE 2023²
The review by Ali et al. was aimed at comparing rates of adverse events in the first 30 minutes following the administration of LUMASON® UEA and Definity®.
The core results were based on a retrospective assessment of data sets from four health systems in the U.S. (Mayo Clinical Enterprise, Avera Health System, Northwell Health, and Wellstar Health) that had recently observed an increase in the incidence of “severe” and “critical” adverse events (SAEs) at a minority of sites in their systems. The study also retrospectively analyzed data that had been prospectively collected during stress echocardiography procedures conducted at the Mayo Clinic.
Finally, the authors conducted a nested case-control study to assess for an association with COVID-19 vaccination status in those patients who had a UEA-associated adverse drug reaction (ADR) after the approval of COVID-19 vaccination in the USA (December 2020) at any Mayo Clinic site.
The review found that a significantly higher rate of severe and critical cardiopulmonary reactions was reported for LUMASON UEA. Moreover, the paper reported that the frequency of serious adverse events following exposure to LUMASON UEA had increased in the last few years, suggesting a possible link with the massive COVID-19 vaccination campaign, and especially with one of the mRNA vaccines.
While the focus of the analysis was on systems that observed an increase in the incidence of SAEs, a comprehensive review of our own safety data from the four systems included in the study shows that only a minority of sites (<15%) experienced SAEs.4 The overall rarity of SAEs occurring within these systems, along with the general limitations of retrospective analyses makes it challenging to draw firm conclusions from the review.
This is the first published review where an increase in the reporting of adverse event frequency for LUMASON UEA has been reported and we are reviewing these findings with the utmost consideration as we work to better understand the methodology used for the review and subsequently any conclusions that can be drawn from the results.
Limitations
Retrospective chart review at all sites
- The investigation was conducted at four health systems, comprising a total of 81 hospitals. As the adverse events were also reported to Bracco’s pharmacovigilance database, we know that only a minority of hospitals (12/81, 15%) experienced one or more adverse events.4
- The majority of the data from this review derives from a retrospective assessment of different types of medical records. However, it is well known that retrospective studies depend on data entered into a clinical database during routine clinical practice and are not collected for research.
- The review indicates that the included hospitals had different documentation practices calling into question whether patient information was harmonized, i.e.:
- Among the critical information that had to be collected was the occurrence of complications within the first 30 minutes of contrast administration. However, when discussing review limitations, the authors mention uncertainty about the ability to categorize the timing of post-contrast events.
- The Authors also report the inability to identify specific symptoms and to categorize the severity of complications.
- Moreover, certain variables that had the potential to impact the outcome of the review might not have been recorded at all. The retrospective nature of the analysis did not make it possible to account for possible differences in baseline patient characteristics and clinical use of the products across the different health systems, and individual hospitals.
- Qualification, training and monitoring of operators in charge of extracting information from the relevant databases is not mentioned which can lead to inconsistencies when making comparisons across these databases.
- Finally, it is unclear whether data abstractors were blind to the purpose of the review and the research questions the review was aimed to address (to avoid reviewers’ bias).
- Among the limitations, it is also mentioned that the frequency of adverse events may have been underestimated. This might have been more likely with an agent like Definity®, in clinical use at various institutions for a long time, longer than that of LUMASON UEA, where this was observed. The researchers also declared back pain and/or headache to not be allergic and not a major focus of the review further reducing calculated adverse event rates for UEA that may be more prone to these adverse drug reactions, such as Definity®.5
- Immediate-type (i.e., within 30 minutes) reactions to ultrasound contrast agents are believed to be a consequence of direct activation of the complement system (complement activation-related pseudo-allergy (CARPA) reactions).6 CARPA reactions resemble true allergic reactions; however, in contrast to immunoglobulin E-mediated type 1 hypersensitivity reactions, in CARPA reactions no prior exposure is necessary, the reaction is typically milder or absent upon repeated exposure, spontaneous resolution often occurs, and there is a higher reaction rate among the general population.6 Women and “atopic” individuals (those with pre-existing allergies) may be at higher risk.7
- In evaluating the review discussion and listing of individual serious adverse events in the Supplemental Table, a proportion of serious adverse events do not appear to be CARPA reactions (non-CARPA events), especially following exposure to LUMASON UEA (19 cases with Definity®, 44 with LUMASON UEA). In these cases, a possible association with the administration of the contrast agent is more difficult to suggest. Of note, the conditions of the patients developing non-CARPA events were not reported nor discussed.
- The different administration schemes were a major confounding factor, especially considering that the dilution and infusion for Definity® was introduced to improve safety and the researchers offered no comparison of CARPA rates with Definity® dilution/bolus vs further dilution/infusion.8
Mayo Clinic Rochester stress echocardiographic database
- Retrospective review of data from a reliable database, composed of prospectively collected information about patients undergoing stress-echo exams.
- The LUMASON UEA and Definity® cohorts showed several major and significant differences (type of stress procedure, patient populations, administration scheme, etc.), which make them difficult to compare.
In summary, given the limitations and currently available information surrounding the methodology it is difficult to draw firm conclusions from the review by Ali et al.
Study by Filippone et al., 2023³
The paper by Filippone et al. reported data from prospective and retrospective clinical studies in critically ill patients at higher than usual risk for developing cardiopulmonary reactions, as well as post-marketing surveillance data up to February 2023.
- No detrimental effects of LUMASON UEA on cardiac electrophysiology were observed in patients with coronary artery disease, and no significant effects on pulmonary hemodynamics were noted in patients with pulmonary hypertension or congestive heart failure.
- Similarly, no effects on several assessments of pulmonary function were observed in patients with chronic obstructive pulmonary disease, and no clinically meaningful changes in oxygen saturation or other safety parameters were observed after administration of LUMASON UEA to patients with diffuse interstitial pulmonary fibrosis.
- The retrospective study of critically ill patients revealed a reduction of in-hospital mortality between patients administered LUMASON UEA for echocardiography versus those who had undergone echocardiography without a contrast agent.
- Post-marketing surveillance revealed very low reporting rates for all serious adverse events (<1 every 10,000 exposures), of which part were due to hypersensitivity to the agent.3
Our Commitment
Bracco is continuing to work closely with the echocardiography community to understand what changes, if any, might be occurring when it comes to the use of ultrasound contrast agents like LUMASON UEA in unique settings and what factors may have led to the observations that have occurred at these select sites.
Additional Resources:
Safety profile of ultrasound enhancing agents in echocardiography
The individual who appears is for illustrative purposes. The person depicted is a model and not a real healthcare professional.
Adverse Reaction in Patients* (n=6856)1
| Number (%) of Patients with Adverse Reactions | 340 (5%) |
|---|---|
| Headache | 65 (1%) |
| Nausea | 37 (0.5%) |
| Dysgeusia | 29 (0.4%) |
| Injection site pain | 23 (0.3%) |
| Feeling hot | 18 (0.3%) |
| Chest discomfort | 17 (0.2%) |
| Chest pain | 12 (0.2%) |
| Dizziness | 11 (0.2%) |
| Injection site warmth | 11 (0.2%) |
* Occurring in at least 0.2% of patients.
LUMASON is an ultrasound contrast agent made up of SF6-filled microspheres
Sulfur hexafluoride gas in LUMASON is inert and undergoes little or no biotransformation1
LUMASON microspheres are constructed of sulfur hexafluoride gas in a highly elastic shell9
- 99% of LUMASON microspheres are ≤10 µm1
- Upper size limit: 100% of LUMASON microspheres are ≤20 µm1
- Designed to be stable and resist pressure changes9
- Acoustic properties constant over the entire range of frequencies used in clinical settings10
LUMASON® is known globally as SonoVue® which has been administered to millions of patients worldwide since its first approval in 2001.11
INDICATIONS AND USAGE | IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS CARDIOPULMONARY REACTIONS
Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following the injection of ultrasound contrast agents, including sulfur hexafluoride lipid microspheres. Most serious reactions occur within 30 minutes of administration.
INDICATIONS AND USAGE | IMPORTANT SAFETY INFORMATION
LUMASON® (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for intravenous use or intravesical use
Indications
LUMASON® (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for intravenous use or intravesical use is an ultrasound contrast agent indicated for use:
- in echocardiography to opacify the left ventricular chamber and to improve the delineation of the left ventricular endocardial border in adult and pediatric patients with suboptimal echocardiograms
- in ultrasonography of the liver for characterization of focal liver lesions in adult and pediatric patients
- in ultrasonography of the urinary tract for the evaluation of suspected or known vesicoureteral reflux in pediatric patients
IMPORTANT SAFETY INFORMATION
WARNING: SERIOUS CARDIOPULMONARY REACTIONS
Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following the injection of ultrasound contrast agents, including sulfur hexafluoride lipid microspheres. Most serious reactions occur within 30 minutes of administration.
- Assess all patients for the presence of any condition that precludes administration
- Always have resuscitation equipment and trained personnel readily available
Contraindications
LUMASON (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for intravenous use or intravesical use is contraindicated in patients with known or suspected hypersensitivity to sulfur hexafluoride lipid microsphere or its components, such as polyethylene glycol (PEG).
Warnings
Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or shortly following administration of ultrasound contrast agents, including LUMASON. Always have cardiopulmonary resuscitation personnel and equipment readily available prior to LUMASON administration and monitor all patients for acute reactions.
Post-marketing hypersensitivity reactions, including serious hypersensitivity reactions, have been observed during use or shortly following LUMASON administration. These reactions may occur in patients with no history of prior exposure to sulfur hexafluoride lipid-containing microspheres. LUMASON contains PEG. There may be increased risk of serious reactions including death in patients with prior hypersensitivity reaction(s) to PEG.
Systemic embolization may occur in patients with cardiac shunts. Assess patients with cardiac shunts for embolic phenomena following LUMASON administration.
There is a risk of ventricular arrhythmia related to high mechanical index in patients administered LUMASON. LUMASON is not recommended for use at mechanical indices greater than 0.8.
The most common adverse reactions (incidence ≥ 0.5%) are headache (1%) and nausea (0.5%).
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.
Please click here for full Prescribing Information for LUMASON ultrasound contrast agent, including BOXED WARNING on Serious Cardiopulmonary Reactions.
LUMASON is manufactured for Bracco Diagnostics Inc., Princeton, NJ 08831 by Bracco Suisse S.A., Plan-les-Ouates Geneve, Switzerland (LUMASON lyophilized powder vial-25 mg lipid-type A/60.7 sulfur hexafluoride gas); Vetter Pharma-Fertigung GmbH & Co. KG, 88212 Ravensburg, Germany (Sodium Chloride 0.9% Injection, USP); B. Braun Melsungen AG, 34212 Melsungen, Germany (Mini-Spike).
LUMASON and SONOVUE are registered trademarks of Bracco Diagnostics Inc. and its affiliated entities.
All other trademarks and registered trademarks are the property of their respective owners.
IMPORTANT SAFETY INFORMATION | INDICATION AND USAGE
WARNING: SERIOUS CARDIOPULMONARY REACTIONS
Serious cardiopulmonary reactions, including fatalities, have occurred uncommonly during or following the injection of ultrasound contrast agents, including sulfur hexafluoride lipid microspheres. Most serious reactions occur within 30 minutes of administration.
References:
1. LUMASON® (sulfur hexafluoride lipid-type A microspheres) for injectable suspension, for intravenous use or intravesical use full Prescribing Information. Princeton, NJ: Bracco Diagnostics Inc.; August 2021.
2. Ali MT, Johnson M, Irwin T, et al. Incidence of severe adverse drug reactions to ultrasound enhancement agents in a contemporary echocardiography practice. J Am Soc Echocardiogr. 2023 Oct 23:S0894-7317(23)00555-2. doi: 10.1016/j.echo.2023.10.010. Epub ahead of print. PMID: 37879379.
3. Filippone A, Kirchin MA, Monteith J, et al. Safety of LUMASON® (SonoVue®) in special populations and critically ill patients. Front Cardiovasc Med. 2023 Aug 2;10:1225654. doi: 10.3389/ fcvm.2023.1225654. PMID: 37600063; PMCID: PMC10433219.
4. Data on file, Bracco Diagnostics Inc., Princeton, NJ.
5. Liu YN, Khangura J, Xie A, et al. Renal retention of lipid microbubbles: a potential mechanism for flank discomfort during ultrasound contrast administration. J Am Soc Echocardiogr. 2013 Dec;26(12):1474-81. doi: 10.1016/j.echo.2013.08.004. Epub 2013 Sep 12. PMID: 24035699; PMCID: PMC3840100.
6. Szebeni J. Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology. 2005 Dec;216(2-3):106-121.
7. Herzog CA. Incidence of adverse events associated with use of perflutren contrast agents for echocardiography. JAMA. 2008;299:2023-5
8. Muskula PR, Main ML. Safety with echocardiographic contrast agents. Circ Cardiovasc Imaging. 2017 Apr;10(4):e005459. doi: 10.1161/CIRCIMAGING.116.005459. PMID: 28377467.
9. Schneider M. Characteristics of SonoVue™. Echocardiography. 1999;16(7, pt 2):743-746.
10. Schneider M, Arditi M, Barrau MB, et al. BR1: a new ultrasound contrast agent based on sulfur hexafluoride-filled microbubbles. Invest Radiol. 1995;30(8):451-457.
11. Data on file. Bracco Diagnostics Inc.