Symptoms Associated With Gadolinium Exposure: Different Patterns and Rates Between Linear and Macrocyclic...

Some patients who received multiple administrations of gadolinium-based contrast agents (GBCAs) have been reported to develop "symptoms associated with gadolinium exposure" (SAGE). The aim of this study was to analyze pharmacovigilance data and to explore the various SAGE patterns of linear and macrocyclic GBCAs among patients exhibiting 3 or more SAGE symptoms.

SAGE were identified from a review of the scientific literature, and the corresponding preferred terms (PTs) were searched in each system organ class recorded in the FDA Adverse Event Reporting System (FAERS). To ensure the comparability of data, 3 macrocyclic and 3 linear extracellular GBCAs currently approved for intravenous administration in the United States were considered. Only patients with 3 or more SAGE symptoms were included. SAGE weights, representing the percentage of SAGE symptoms among all adverse events collected over a 6-year period from 2014 to 2019, were calculated for each GBCA. The frequency of these symptoms to occur in sets of "3 PT combinations" was also analyzed. The 3 PT combinations were calculated by first selecting the PT with the highest occurrence for a GBCA and then combining it with all the PTs accounting for 5% or more of the total adverse events reported for the respective GBCA. This led to identify the most prevalent 3 PT combinations per GBCA. Moreover, in order to determine whether or not SAGE symptoms were specific to GBCAs, data for 4 water-soluble iodinated contrast media were also extracted from the FAERS database over the same period, using the SAGE list of symptoms as reference.

The analysis of FAERS data revealed a significantly higher SAGE weight for the linear GBCAs (20%-24%) than for the macrocyclic GBCAs (5%-9%). For the linear agents, the most prevalent 3 PT combinations of SAGE symptoms were reported in 152-164 occurrences, whereas for the macrocyclic agents, this range was significantly lower (1-13 occurrences). Moreover, all these agents could be categorized in 3 groups with different patterns of 3 PT combinations (ie, [gadodiamide and gadopentetate dimeglumine], [gadobenate dimeglumine and gadoteridol], and [gadoterate dimeglumine and gadobutrol]). The most prevalent PTs were found to be "pain," "arthralgia," and "headache" in each group, respectively.

The global SAGE weights were significantly lower for the macrocyclic GBCAs as compared with the linear GBCAs. Moreover, the frequency of occurrence of 3 PT combinations was notably lower with the macrocyclic agents and comparable to the iodinated contrast media, indicating that SAGE may be negligible for this class of GBCAs. Different patterns of 3 PT combinations were also observed among the GBCAs involved in this study. A causal relationship could not be established between SAGE and the corresponding GBCAs, therefore, further research on this topic and routine pharmacovigilance are warranted.