Safety Of Gadobutrol Research Articles

GADOLINIUM-INDUCED CARDIOPULMONARY ARREST IN A 57-YEAR-OLD FEMALE

TOPIC: Allergy and Airway TYPE: Medical Student/Resident Case Reports INTRODUCTION: Magnetic resonance contrast agents are used to better characterize disease processes during Magnetic Resonance Imaging (MRI). Gadolinium based contrast agents (GBCA) are widely used due to their safety profile. The incidence of adverse events after receiving GBCAs is less than 2%, most being mild and transient [1,2]. Here, we see a patient who developed cardiopulmonary arrest after GBCA administration. CASE PRESENTATION: A 57 year old female with a past medical history of asthma, hypertension, diabetes, hyperlipidemia and mild COVID19 infection, presented to outpatient brain MRI for evaluation of new hearing loss. After receiving Gadobutrol, she developed shortness of breath, abdominal pain, and emesis. In the emergency department, the patient was hypothermic, tachypneic, and hypoxic;no urticaria or rash noted. She was placed on non-invasive ventilation and treated for presumed anaphylaxis, but remained hypoxic and in respiratory distress. Subsequent intubation (without angioedema visualized) was complicated by cardiac arrest, requiring six minutes of cardiopulmonary resuscitation. Initial imaging was significant for CT chest showing diffuse ground glass and consolidative opacities and normal CT head. Despite standard care treatment, the patient's neurological exam worsened, one week into her admission she was observed to have minimal brainstem reflexes, with head CT showing findings of anoxic brain injury, cerebral edema and possible uncal herniation. She worsened clinically and expired thirteen days after admission. Autopsy performed showed clinicopathological correlation attributing anoxic brain injury secondary to anaphylaxis. DISCUSSION: Gadobutrol is approved for multiple indications in most ages. It was introduced in 1998, its safety profile has been studied in patients worldwide. The incidence of adverse events of GBCA has been reported to be 0.32-3.8%, commonly nausea, vomiting, urticaria and dizziness. Risk factors include patients' history of respiratory allergic disease, asthma, COPD, or prior history of reactions to iodinated contrast media [1,2]. The incidence of serious adverse drug reactions (ADR) involving the cardiopulmonary system is reported to be <0.1%;from 1998-2012 there were 614 cases of ADR of which 7.2% were fatal [3]. Our case presentation shows a severe ADR to gadolinium contrast for MRI. Though the patient's pre-existing history of asthma put her at slightly higher risk, proven safety of gadolinium contrast significantly weighs towards continued use of contrast enhanced MRI. Nevertheless, awareness and timely response to possible contrast-induced ADR is important for all clinicians. CONCLUSIONS: GBCA are widely used agents with good safety profiles. Although severe adverse events are rare, it's important for physicians to have a high index of suspicion and use caution in patients that are identified with risk factors for adverse reactions to these agents. REFERENCE #1: [1] Marie-France Bellin. MR contrast agents, the old and the new. European Journal of Radiology volume 60, Issue 3, 2006, 314-323. doi.org/10.1016/j.ejrad.2006.06.021. REFERENCE #2: [2] Endrikat, Jan MD, PhD*†;Vogtlaender, Kai PhD‡;Dohanish, Susan RA§;Balzer, Thomas MD, PhD∥;Breuer, Josy MD, PhD*Safety of Gadobutrol, Investigative Radiology: September 2016 - Volume 51 - Issue 9 - p 537-543 doi: 10.1097/RLI.0000000000000270 REFERENCE #3: [3] Raisch, D. W., Garg, V., Arabyat, R., Shen, X., Edwards, B. J., Miller, F. H.,… West, D. P. (2013). Anaphylaxis associated with GADOLINIUM-BASED contrast AGENTS: Data from the food and DRUG Administration's adverse event reporting system and review of case reports in the literature. Expert Opinion on Drug Safety, 13(1), 15-23. doi:10.1517/14740338.2013.832752 DISCLOSURES: No relevant relationships by Lauren Blackwell, source=Web Response No relevant relationships by Rostislav Gorbatov, source=Web Response No relevant relationships by Chinazor Iwuaba, source=Web Response

Safety of gadobutrol: results of a non-interventional study of 3710 patients, including 404 children.

BackgroundThe safety of gadolinium-based contrast agents is a hot topic in radiology.PurposeTo evaluate the safety profile of gadobutrol during routine use.Material and MethodsProspective, non-interventional study in 80 centers in Germany. The primary outcome was the number of adverse drug reactions (ADR) following gadobutrol administration.ResultsA total of 3710 patients were included in the analysis, including 404 children (10.9%). A total of 6026 magnetic resonance imaging examinations of organs/organ systems and 872 magnetic resonance angiography examinations were performed. A total of 22 (0.59%) patients experienced at least one ADR. Nausea and vomiting were the most frequent ADRs, experienced by nine (0.24%) and three (0.08%) patients, respectively. One serious ADR was recorded (anaphylactoid reaction). No deaths were reported.ConclusionThis non-interventional study in 3710 patients confirmed gadobutrol as a safe and reliable contrast agent in adults and children.

Safety of gadobutrol in more than 1,000 pediatric patients: subanalysis of the GARDIAN study, a global multicenter prospective non-interventional study.

BackgroundGadobutrol is a gadolinium-based contrast agent, uniquely formulated at 1.0 mmol/ml. Although there is extensive safety evidence on the use of gadobutrol in adults, few studies have addressed the safety and tolerability of gadobutrol in pediatric patients.ObjectiveThis subanalysis of data from the GARDIAN study evaluated the safety and use of gadobutrol in pediatric patients (age <18 years).Materials and methodsThe GARDIAN study was a large phase IV non-interventional prospective multicenter post-authorization safety study performed in Europe, Asia, North America and Africa. A total of 23,708 patients were included who were scheduled to undergo cranial or spinal MRI, liver or kidney MRI, or MR angiography with gadobutrol enhancement. The primary study endpoint was the overall incidence of adverse drug reactions (ADRs) and serious adverse events (SAEs) following gadobutrol administration.ResultsThe GARDIAN study included 1,142 children (age <18 years) who received gadobutrol at a mean dose of 0.13 (range 0.04–0.50) mmol/kg body weight. Gadobutrol was well tolerated in these children, with low rates of ADRs (0.5%) and no SAEs, consistent with results in adults enrolled in the GARDIAN study. Rates of adverse events and ADRs were unrelated to pediatric age or gadobutrol weight-adjusted dose. There were no symptoms suggestive of nephrogenic systemic fibrosis. Investigators rated the contrast quality of gadobutrol-enhanced images as good or excellent in 97.8% of pediatric patients, similar to the main study population.ConclusionGadobutrol is very well tolerated and provides excellent contrast quality at the recommended weight-adjusted dose in children (age <18 years), similar to the profile in adults.

Safety of gadobutrol in over 23,000 patients: the GARDIAN study, a global multicentre, prospective, non-interventional study

ObjectivesTo investigate the safety and tolerability of gadobutrol at the recommended dose in patients requiring contrast-enhanced magnetic resonance imaging/angiography (MRI/MRA) in the routine setting.MethodsGARDIAN prospectively enrolled 23,708 patients undergoing routine gadobutrol-enhanced MRI/MRA for approved indications at 272 study centres in Europe, Asia, North America, and Africa and monitored for adverse events.ResultsMedian gadobutrol dose was 0.11 mmol/kg body weight. The overall incidence of adverse drug reactions (ADRs) was 0.7 % (n = 170 patients), with similar incidences in patients with renal impairment or cardiac disease, from different geographic regions and in different gadobutrol dose groups. Patients at risk for contrast media reaction had an ADR incidence of 2.5 %. Five patients (0.02 %) experienced serious adverse events, four were drug-related. One patient experienced a fatal anaphylactoid shock, assessed to be related to injection of gadobutrol. The contrast quality of gadobutrol-enhanced images was rated by treating physicians as good or excellent in 97 % cases, with similar ratings in all patient subgroups and indications.ConclusionsThe GARDIAN study shows that gadobutrol at the recommended dose is well tolerated across a large, diverse patient population.Key points• Gadobutrol at recommended dose shows low rates of adverse drug reactions• Gadobutrol demonstrates a uniform safety profile across diverse patient groups• Gadobutrol provides excellent contrast quality in routine practice

A multicenter, randomized, controlled, single‐blind comparison phase III study to determine the efficacy and safety of gadobutrol 1.0 M versus gadopentetate dimeglumine following single injection in patients referred for contrast‐enhanced MRI of the body regions or extremities

To demonstrate the noninferiority of gadobutrol-enhanced magnetic resonance imaging (MRI) compared with gadopentetate dimeglumine-enhanced MRI in Asian patients referred for contrast-enhanced imaging of the body or extremities. A multicenter, parallel-group comparison study of Asian adults referred for contrast-enhanced MRI were randomized (1:1) to either gadobutrol or gadopentetate dimeglumine. Lesions were assessed for three primary visualization variables: degree of contrast enhancement, border delineation, and internal morphology. Secondary efficacy variables included number of lesions detected, match of MRI diagnosis with final clinical diagnosis, and sensitivity and specificity for malignant lesion detection. Safety was monitored for 24 ± 4 hours after contrast agent administration. A total of 363 patients received either gadobutrol (n = 168) or gadopentetate dimeglumine (n = 178). Mean total scores for three primary visualization variables were 9.39 and 9.34 for gadobutrol and gadopentetate dimeglumine, respectively. The proportion of patients with matched MRI and final diagnosis and sensitivity for malignant lesion detection was greater for unenhanced versus combined images (gadobutrol: 72.2% vs. 81.7%; gadopentetate dimeglumine: 76.2% vs. 82.2%, respectively). Both contrast agents were well tolerated. Gadobutrol (0.1 mmol/kg BW) was well tolerated and effective in Asian patients referred for contrast-enhanced MRI of the body or extremities.

Overview on the efficacy and safety of gadobutrol: an MRI contrast agent for the CNS, body and vessels

Contrast-enhanced MRI has become a mainstay of clinical imaging with unlimited applications. However, a limitation of conventional contrast agents in MRI is the insufficient signal-to-noise ratios due to relaxivity. Gadobutrol (1.0 mmol/ml), an extracellular macrocyclic contrast agent of high stability, is indicated for contrast-enhanced MRI of adults, adolescents and children 2 years of age and older. Gadobutrol offers increased T1 relaxivity, which improves MR image quality and clinical use of the technique.

Efficacy and Safety of Gadobutrol (1.0 M) versus Gadopentetate Dimeglumine (.5 M) for Enhanced Mri of Cns Lesions: A Phase Iii, Multicenter, Single-blind, Randomized Study in Chinese Patients

The aim of this study was to compare the efficacy and safety of macrocyclic gadobutrol (1.0 M) with linear gadopentetate dimeglumine (0.5 M) for contrast-enhanced magnetic resonance imaging (MRI) of central nervous system (CNS) lesions in Chinese patients (N = 147) with known or suspected CNS lesions, who were enrolled in this single-blind, randomized, parallel-group study. Three blinded independent readers evaluated all efficacy variables. The primary efficacy variable was the difference between the two agents for the change in contrast-to-noise ratio (CNR) between non-enhanced and contrast-enhanced scans of lesions. Secondary outcomes included mean change in number of lesions detected before and after contrast enhancement, diagnostic confidence, and safety and tolerability parameters. Gadobutrol was non-inferior to gadopentetate dimeglumine in respect to the difference in the mean change in CNR (6.94; 95% confidence interval [CI] lower limit: -3.90; predefined maximum 95% CI lower limit: -6.52). The mean change in the number of CNS lesions detected was greater with gadobutrol versus gadopentetate dimeglumine (1.2 vs. 0.2 lesions). Diagnostic confidence was classified as ‘high’ for more patients with gadobutrol versus gadopentetate dimeglumine by the investigators (58.8% vs. 55.4%) and by the three blinded readers (63.6% vs. 55.7%, 23.7% vs. 18.0% and 81.7% vs. 81.0%). Both agents were well tolerated by participating patients. We concluded that in Chinese patients with CNS lesions, gadobutrol (1.0 M) was as effective and well tolerated in contrast-enhanced MRI as gadopentetate dimeglumine (0.5 M). Gadobutrol provided improved visualization of CNS lesions compared with gadopentetate dimeglumine, with a comparable tolerability profile.

Pharmacokinetics and Safety of Gadobutrol-Enhanced Magnetic Resonance Imaging in Pediatric Patients

This clinical study investigated the pharmacokinetics and safety of gadobutrol, a magnetic resonance (MR) imaging extracellular contrast agent, in pediatric patients aged 2 to 17 years. In this open-label, multicenter study, patients scheduled for routine contrast-enhanced MR imaging of the brain, spine, liver or kidney, or MR angiography received a single intravenous injection of gadobutrol (0.1 mmol/kg/0.1 mL/kg). Patients were stratified by age groups (2-6, 7-11, and 12-17 years). Blood and urine samples were collected at prespecified time points and analyzed for gadolinium concentrations. Plasma data were evaluated by means of a nonlinear mixed effects model, and urine data were analyzed using descriptive statistics. In addition, the safety of gadobutrol was evaluated. A total of 130 patients (2-6 years, n = 45; 7-11 years, n = 39; 12-17 years, n = 46) were included in the final population pharmacokinetic analysis. Gadobutrol pharmacokinetics in children aged 2 to 17 years were adequately described by an open 2-compartment model with elimination from the central compartment. The median estimates (2.5th percentile, 97.5th percentile) of body weight-normalized total body clearance (L/h/kg) per age group were 0.10 (0.05, 0.17) for all ages, 0.13 (0.09, 0.17) in the 2 to 6 year age group, 0.10 (0.05, 0.17) in the 7 to 11 year age group and 0.09 (0.05, 0.10) in the 12 to 17 year age group. The body weight-normalized median estimates of total volume of distribution (L/kg) were 0.20 (0.12, 0.28) for all ages, 0.24 (0.20, 0.28) in the 2 to 6 year age group, 0.19 (0.14, 0.23) in the 7 to 11 year age group and 0.18 (0.092, 0.23) in the 12 to 17 year age group. Median gadolinium plasma concentrations at 20 minutes postinjection were simulated using the population pharmacokinetic model and ranged from 414 (13 kg subject) to 518 micromol/L (65 kg subject). Body weight was identified as the major covariate influencing the pharmacokinetic parameters of total body clearance and central volume of distribution. Age was not found to be an additional independent parameter. The median amount of renally excreted gadolinium was 77.0% of the administered dose within 6 hours postinjection, indicating that gadobutrol was renally excreted in this pediatric population aged 2 to 17 years. Gadobutrol was well tolerated, with drug-related adverse events of mild intensity reported for 8 (5.8%) of 138 patients. Observed differences in pharmacokinetics were attributed to body weight, with no additional independent effect of age. Thus, no dose adjustment from the standard dose of gadobutrol in adults based on body weight (0.1 mmol/kg) is necessary in pediatric patients aged 2 to 17 years. Gadobutrol was safe and well tolerated in the pediatric population in this study.