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ObjectiveThe aim of this study was to provide a systematic safety analysis of gadobutrol after more than 29 million applications in clinical routine.Materials and MethodsForty-two clinical development phase II to IV studies on gadobutrol or comparator and the postmarketing safety surveillance database for gadobutrol (1998–2015) were analyzed. Adverse events (AEs) and drug-related AEs were evaluated in the clinical development database and spontaneous adverse drug reactions (ADRs) in the postmarketing database. Subgroup analyses were run on patients with special medical history and on patients of different age groups.ResultsIn the clinical development studies, 6809 and 2184 patients received gadobutrol or comparators, respectively. The incidence of drug-related AEs was 3.5% for both groups. With the exception of nausea (0.7% related cases in both groups), all other drug-related AEs were 0.3% or less in both groups. Hypersensitivity reactions were sporadic (<0.1%). Patients with history of allergies to contrast agents experienced slightly more drug-related AEs. No differences were seen between age groups.The overall reporting rate of ADRs from postmarketing surveillance was 0.05%. The most frequent ADRs were anaphylactoid/hypersensitivity reactions, nausea, vomiting, and dyspnea.For 3 single-agent reports of nephrogenic systemic fibrosis, using a conservative approach, association with gadobutrol could not be excluded.ConclusionsGadobutrol is well tolerated and has a favorable safety profile for patients of all age groups.

Purpose: To summarize the safety data of gadoxetate disodium, reported in 12 Phase II and III clinical development studies and in the postmarketing surveillance database. Materials and Methods: Patients with liver lesions received gadoxetate disodium-enhanced liver magnetic resonance imaging (MRI). Adverse events (AEs) were recorded and evaluated with regard to a potential drug relationship. Subgroup analyses were run on patients with special medical history. Worldwide spontaneous AEs and adverse drug reactions (ADRs) from postmarketing safety surveillance were analyzed. Results: A total of 1989 patients were included in the clinical development program. A total of 1581/1989 (79.5%) patients received the finally approved dose of 0.025 mmol/kg body weight. 10.1% of patients reported AEs, 4.1% were classified as related AEs. Nausea and headache were the most frequently reported related AEs, with 1.1% each. Age, history of contrast media allergy, liver cirrhosis, or impaired liver or renal function did not significantly impact the frequency and type of AEs. The postmarketing safety surveillance database encompassed more than 2.2 million patients. Nausea was the most frequent ADR, with a reporting rate of 0.00652%; all other symptoms were below 0.004%. Conclusion: Gadoxetate disodium for liver MRI has an excellent safety profile. G adoxetate disodium is a magnetic resonance imaging (MRI) contrast agent developed for detection, localization, and characterization of liver lesions.Gadoxetate disodium belongs to the class of linear ionic gadolinium-based contrast agents (GBCAs). The contrastenhancing effect is mediated by the gadolinium complex gadolinium-ethoxybenzyl-diethylene-triamine penta-aceticacid (Gd-EOB-DTPA). It features a high T 1 relaxivity of 6.9 L mmol 21 s 21 at 1.5T (in plasma). 1,2 After intravenous application, gadoxetate disodium is distributed in the extracellular space and selectively taken up by the hepatocytes, thus providing both dynamic and hepatocyte-specific imaging. In healthy patients about 50% is excreted via the kidneys and 50% via the biliary system. 3,4 Signal enhancement of the liver parenchyma and liver-to-lesion contrast starts within 10 minutes and is highest at about 20 minutes after administration with a plateau lasting for at least to 45 minutes postinjection. 5,6The safety profile of gadoxetate disodium has been demonstrated in several (controlled) clinical studies 7-9 and in postmarketing studies. So far, since approval in March 2004 through March 2014, more than 2.2 million patients have been exposed to gadoxetate disodium worldwide. The purpose of this evaluation was to systematically summarize the safety data of gadoxetate disodium collected in Phase II and III clinical development studies and additionally to analyze 10-year results from the global postmarketing surveillance database.View this article online at wileyonlinelibrary.com.

BackgroundSafety data on routine clinical use of gadoxetate disodium for liver magnetic resonance imaging (MRI) is not reported yet.PurposeTo assess the safety profile of gadoxetate disodium for liver MRI in the routine clinical setting.Material and MethodsSix multicenter studies were performed in Europe, USA, Australia, and Asia to evaluate the safety and efficacy of gadoxetate disodium (Primovist®/Eovist®) enhanced liver MRI. Patients received a single intravenous bolus injection of the standard approved dose of 0.025 mmol/kg body weight (0.1 mL/kg). The number of patients, the characteristics of adverse events, related adverse events, and serious adverse events were analyzed.ResultsA total of 8194 patients were included in the database. A total of 141 patients (1.7%) reported 230 AEs of which 129 were considered being related to the use of gadoxetate disodium by the investigators. None of the AEs in the pediatric population (n = 52) were related. The most frequent AEs independent of relationship to the drug included dyspnea (25/0.31%), nausea (22/0.27%), liver disorders (13/0.16%), and renal disorders (9/0.11%). Nine related SAEs were recorded. No patient died during the studies.ConclusionGadoxetate disodium for liver MRI is safe and well tolerated in the routine clinical setting.

ObjectivesThe aim of this study was to critically assess the evaluation and categorization process for nephrogenic systemic fibrosis (NSF) based on reports received by Bayer from 2006 to 2016.Materials and MethodsA total of 779 NSF reports received by Bayer globally from 2006 to 2016 were included in the analysis. Arlington Medical Resources provided gadolinium-based contrast agent (GBCA) market share. Reports were conservatively categorized based on the Cowper/Girardi criteria. A statistical model simulated the impact of market share and market introduction on the number of unconfounded reports.ResultsFor all reports, reported onset of disease ranged from 1996 and 2012. Of 779 reports, 325 involved a Bayer product only, 208 involved only products from other companies (or unknown GBCA), and 246 involved both Bayer and non-Bayer products. Most of all reports (86%) originated from the United States.Through 2006, Magnevist and Omniscan dominated the US market (>80% combined market share). All other GBCAs with fewer NSF reports comprised the remaining combined market share of less than 20% or were introduced after May 2007, after safety recommendations came into effect.A total of 563 reports (220 single-agent and 343 multiagent reports) involved Magnevist. In at least 150 of the 343 reports, a different GBCA (Omniscan, 118; OptiMARK, 15; MultiHance, 6; and macrocyclic agent, 11) showed the closest temporal relationship to onset of NSF-like symptoms.The simulation model demonstrated that patients receiving a GBCA with lower market share and late market introduction are less likely to be observed in an unconfounded setting.ConclusionsYear of market introduction, as well as US market share in 2000 to 2007, greatly influenced the absolute number of NSF reports for each GBCA, their a priori probability to cause NSF, as well as their a priori probability to be associated with unconfounded cases of NSF. Variability in case interpretation and pharmacovigilance approaches also influence the absolute number of unconfounded cases and should therefore not be used for comparative risk assessments. This should be primarily based on objective product parameters such as structure, stability, pharmacokinetics, and dose.