Gadolinium retention after administration of contrast agents based on linear chelators and the recommendations of the European Medicines Agency

Abstract

The Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) earlier this year recommended to suspend some marketing authorisations for Gadolinium Containing Contrast Agents (GCCAs) based on linear chelators due to the potential risk of gadolinium retention in the human body. These recommendations have recently been re-evaluated by EMA's Committee for Medicinal Products for Human Use (CHMP), and confirmed the final opinion of the European Medicines Agency. This editorial provides an overview of the available GCCAs and summarises the recent evidence of gadolinium retention. Moreover, a critical appraisal of the strengths and limitations of the scientific evidence currently available on gadolinium retention is given. Key points • EMA recommended suspension of some EU marketing authorisations of four linear GCCAs. • Brain MRI findings indicating gadolinium retention have been confirmed by mass spectrometry.• Current scientific evidence for gadolinium retention has several methodological limitations.• No clear clinical evidence exists indicating that gadolinium retention causes neurotoxicity.• Long-term safety of GCCAs, however, remains unclear.

Absence of dentate nucleus resting‐state functional connectivity changes in nonneurological patients with gadolinium‐related hyperintensity on T1‐weighted images

“…12,13 GBCAs with a linear structure have shown higher propensity to brain long-term retention than those with a cyclic structure and higher kinetic and thermodynamic stability. [1][2][3][4][5][6][7] The most influential regulatory agencies and institutions in medicine and radiology worldwide, including the European Medicine Agency (EMA), 14 US Food and Drug Administration (FDA), 15 American College of Radiology together with the American Society of Neuroradiology, 16 as well as the International Society for Magnetic Resonance in Medicine (ISMRM) 17 have debated on different aspects of this issue, but consistently concluded that no adverse effects on brain function have been identified to date. However, there remains concern on the eventual increased risk of neurocognitive consequences of gadolinium deposition in the brain.…”

Abbreviated MRI of the Breast: Does It Provide Value?

“…To date, the clinical significance of the brain retention of GBCAs is unknown, and there is no scientific evidence of adverse clinical effect. Nevertheless, the recent controversy about the safety of GBCAs has sparked the recommendation to use GBCAs only when essential diagnostic information cannot be obtained with unenhanced scans . This is particularly relevant for the field of breast imaging where healthy women are screened for breast cancer with DCE‐MRI.…”

“…Nevertheless, the recent controversy about the safety of GBCAs has sparked the recommendation to use GBCAs only when essential diagnostic information cannot be obtained with unenhanced scans. 66,74 This is particularly relevant for the field of breast imaging where healthy women are screened for breast cancer with DCE-MRI. Therefore, there are considerable efforts to develop unenhanced MRI techniques with equal sensitivity for breast MRI screening.…”

Gadolinium(III)‐Based Dual 1H/19F Magnetic Resonance Imaging Probes

“…Indeed, some toxicity problems have been attributed to the dissociation of GdCAs, most often after administration of non‐macrocyclic derivatives . As a consequence of these toxicity issues, restrictions and suspensions of authorizations of some linear GdCAs have recently been imposed by the European Medicines Agency . These restrictions do not affect macrocyclic agents, which are kinetically more inert than the linear ones .…”

“…[6] As ac onsequenceo ft hese toxicity issues, restrictions and suspensionso fa uthorizations of some linear GdCAs have recently been imposed by the European Medicines Agency. [7] These restrictions do not affect macrocyclica gents, whicha re kinetically more inert than the linear ones. [8] Another disadvantage of traditional T 1 CAs is the presence of ab ackground signald ue to the bulk water.…”