A Review of FDA Pharmacovigilance Database to Assess the Importance of Symptoms Associated with Gadolinium Exposure (SAGE)
A Review of FDA Pharmacovigilance Database to Assess the Importance of Symptoms Associated with Gadolinium Exposure (SAGE)
Imran Shahid, Eric Lancelot
- The aim of this study was to appreciate the importance of the clinical manifestations in the overall population by assessing the weight of SAGE among the bulk of safety experiences reported to the North American pharmacovigilance database. - SAGE symptoms were searched by preferred terms (PTs) in different system organ class (SOC) categories in the FDA Adverse Event Reporting System (FAERS) database. - To ensure the comparability of the data, three macrocyclic GBCAs, known to possess high kinetic stabilities, namely gadoteridol (Prohance, Bracco), gadobutrol (Gadovist/Gadavist, Bayer Healthcare), gadoterate meglumine (Dotarem, Guerbet; Clariscan, GE Healthcare), and three linear (open chain) GBCAs, namely gadobenate dimeglumine (Multihance, Bracco), gadodiamide (Omniscan, GE) and gadopentetate dimeglumine (Magnevist, Bayer) were selected, Figure 1.†5 - A 5-year period was selected, ranging from 2014 to 2019, to generate time curves and a series of radar and bar charts to compare the selected GBCAs for their SAGE weights.
- Since their use in CE-MRI,† gadolinium based contrast agents (GBCAs) have shown an excellent safety profile with a low incidence of mild adverse events (AEs), rare cases of severe hypersensitivity reactions, and infrequent episodes of neurotoxic reactions [1]. - In 2016, the term “gadolinium deposition disease” (GDD) was proposed to describe a series of symptoms reported by patients with normal renal function after exposure to GBCAs [2]. - In 2021, the term “symptoms associated with gadolinium exposure” (SAGE) was proposed to replace GDD. It refers to symptoms that may occur irrespective of kidney function and are unrelated to established early onset AEs (occurring 24 hours after GBCA exposure, such as nephrogenic systemic fibrosis) [3]. - In 2022, Shahid et al. reported the proclivity of GBCAs to exhibit SAGE symptoms as SAGE weights, after reviewing the pharmacovigilance databases of EMA and FDA,† and demonstrated that the linear GBCA showed significantly higher SAGE weight as compared to the macrocyclic GBCAs [4]. - The most prevalent SAGE symptoms were selected after an in depth review of literature. - The extraction and analysis of adverse events in FAERS revealed a significantly higher SAGE weight for linear GBCAs, namely gadodiamide (23.27%), gadopentetate dimeglumine (22.12%) and gadobenate dimeglumine (19.27%), as compared to the macrocyclic GBCAs, namely gadoteridol (8.45%), gadobutrol (4.53%) and gadoterate meglumine (3.82%), Figure 2. - The SOCs “musculoskeletal and connective tissue disorders”, “nervous system disorders”, “general disorders and administration site conditions” and “psychiatric disorders” were consistent with this ranking, Figures 3-6. - Over the 5 year period, SAGE weights displayed a steady growth of about 5% per year for the linear GBCAs and 1% per year for the macrocyclic agents, Figure 7.
Figure 1. Structures and kinetic stabilities of the macrocyclic and linear GBCAs assessed in the current analysis.†5
Figure 2. Overall SAGE weights of GBCAs.
Figure 3. Bar chart of SAGE weight in the SOC “musculoskeletal and connective tissue disorders”
Figure 4. Radar chart of SAGE weight in the SOC “musculoskeletal and connective tissue disorders”
Figure 5. Bar chart of SAGE weight in the SOC “nervous system disorders"
Figure 6. Radar chart of SAGE weight in the SOC “nervous system disorders"
Figure 7. Time curves demonstrating SAGE weights (%) over a 5 year period (2014 – 2019) for the three macrocyclic and the three linear GBCAs.
- This study showed that SAGE symptoms may be more prevalent with linear than macrocyclic GBCAs, and that SAGE reporting tends to rise significantly more in patients exposed to linear agents. - The differences in SAGE weights might be explained by the differences in kinetic stability between the GBCAs.
