Use of Real-Life Safety Data From International Pharmacovigilance Databases to Assess the Importance of Symptoms Associated With Gadolinium Exposure

Abstract

Objective Recent scientific publications have reported cases of patients who complained from a variety of symptoms after they received a gadolinium-based contrast agent (GBCA). The aim of this study was to appreciate the importance of these clinical manifestations in the overall population by assessing the weight of “symptoms associated with gadolinium exposure” (SAGE) among the bulk of safety experiences reported to major health authorities. Materials and Methods Symptoms associated with gadolinium exposure were identified from a review of the scientific literature, and the corresponding preferred terms were searched in each system organ class (SOC) category recorded in the European and North American pharmacovigilance databases EudraVigilance (EV) and FDA Adverse Event Reporting System (FAERS), respectively. The numbers of SAGE per preferred term, and cumulatively per SOC, were recorded and their weights in the overall spectrum of adverse events (AEs) were determined for each GBCA. Results The analysis of the selected AEs revealed a significantly higher SAGE weight for gadobenate dimeglumine (EV: 25.83%, FAERS: 32.24%) than for gadoteridol (EV: 15.51%; FAERS: 21.13%) and significantly lower SAGE weights for gadobutrol (EV: 7.75%; FAERS: 13.31%) and gadoterate meglumine (EV: 8.66%; FAERS: 12.99%). A similar ranking was found for most of the SOCs except for “nervous system disorders,” probably owing to a limitation in the methods of data selection. Furthermore, this analysis showed a greater percentage of reports mentioning a decrease in the quality of life of the patients when they were exposed to gadobenate dimeglumine or gadoteridol than to gadobutrol or gadoterate meglumine. Conclusion This study showed that SAGE represent a significant percentage of the bulk of AEs reported to the health authorities for each GBCA. It provided real-life arguments suggesting that SAGE may be more prevalent with linear than macrocyclic GBCAs and that gadoteridol may present a higher SAGE risk than the other macrocyclic contrast agents.

Commentary on the Association of Symptoms Associated With Gadolinium Exposure/Gadolinium Deposition Disease and Gadolinium-Based Contrast Agents

“…In summary, our opinion is that, in this report, 1 the data from EV/ FAERS that MultiHance has a high rate of occurrence of SAGE/GDD are correct and concur with our real-world data. The authors conclude that ProHance has a higher SAGE occurrence rate, distinct from our findings.…”

“…The major problems with the FAERS and EV data are no medical confirmation, duplicate reporting, incomplete reporting, and severity and duration of symptoms not established 1–3 …”

“…In this issue of Investigative Radiology , Shahid et al 1 reported the importance of clinical manifestations in the overall population after receiving gadolinium-based contrast agents (GBCAs). The authors have generated a vital study organizing and documenting symptom descriptions for what they call symptoms associated with gadolinium exposure (SAGE), as reported to the regulatory agencies of the European Medicines Agency (EudraVigilance [EV] reporting) 2 and the Federal Drug Agency (FDA Adverse Event Reporting System [FAERS] reporting) 3 .…”

“…Three hundred seventy-five members responded to this request. We did not provide any information about what we were looking for, including the frequency of agents resulting in GBCA from either this report 1 or our data, so that the members were blinded to expected results.…”

Artificial Contrast

“…19 There is still no reliable evidence of a clinical correlate of these gadolinium deposits. Despite the lack of scientific proof of a causal relationship in the absence of an unethical randomized, double-blind study, the growing number of "symptoms associated with gadolinium exposure" 20 urges prudent risk-benefit consideration. The principle of preventing harm to the patient always applies.…”