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On Monday, May 22, 2017, the FDA issued its second Safety Announcement about gadolinium retention in the brain. The following text is the FDA’s complete announcement.
FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue
This is an update to the FDA Drug Safety Communication: FDA evaluating the risk of brain deposits with repeated use of gadolinium-based contrast agents for magnetic resonance imaging (MRI)issued on July 27, 2015.
A U.S. Food and Drug Administration (FDA) review to date has not identified adverse health effects from gadolinium retained in the brain after the use of gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI). All GBCAs may be associated with some gadolinium retention in the brain and other body tissues. However, because we identified no evidence to date that gadolinium retention in the brain from any of the GBCAs, including GBCAs associated with higher retention of gadolinium, is harmful, restricting GBCA use is not warranted at this time. We will continue to assess the safety of GBCAs and plan to have a public meeting to discuss this issue in the future.
Our recommendations for health care professionals and patients remain unchanged from July 2015 when we informed the public that we were investigating this potential risk with GBCAs. As is appropriate when considering the use of any medical imaging agent, health care professionals should limit GBCA use to circumstances in which additional information provided by the contrast agent is necessary, and assess the necessity of repetitive MRIs with GBCAs. Patients, parents, and caregivers should talk to their health care professionals if they have any questions or concerns about the use of GBCAs with MRIs. Retention of gadolinium affects only GBCAs, and does not apply to other types of scanning agents used for other imaging procedures, such as those that are iodine-based or radioisotopes.
GBCAs contain gadolinium, a type of heavy metal, that is linked to a carrier molecule. MRIs are a way to scan the body for problems such as cancer, infections, or bleeding. GBCAs are injected into a vein to enhance the quality of the MRI images of internal organs, blood vessels, and tissues, which helps health care professionals diagnose medical conditions. There are two types of GBCAs based on their chemical structures, linear GBCAs and macrocyclic GBCAs.
We evaluated scientific publications1-17 and adverse event reports submitted to FDA. Some human and animal studies looked at GBCA use over periods longer than a year. These publications and reports show that gadolinium is retained in organs such as the brain, bones, and skin. The publications show that linear GBCAs retain more gadolinium in the brain than macrocyclic GBCAs. However, our review did not identify adverse health effects related to this brain retention.
To date, the only known adverse health effect related to gadolinium retention is a rare condition called nephrogenic systemic fibrosis (NSF) that occurs in a small subgroup of patients with pre-existing kidney failure. NSF is a painful skin disease characterized by thickening of the skin, which can involve the joints and cause significant limitation of motion within weeks to months. Recent publications report cases of reactions involving thickening and hardening of the skin and other tissues in patients with normal kidney function who received GBCAs and did not have NSF; some of these patients also had evidence of gadolinium retention.3, 12, 16 We are continuing to evaluate such reports to determine if these fibrotic reactions are an adverse health effect of retained gadolinium.
The manufacturer of OptiMARK (gadoversetamide), a linear GBCA, updated its label with information about gadolinium retention in various body organs such as the brain, skin, and other organs. We are reviewing the labels of other GBCAs to determine if changes are needed.
A recent review by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA) also identified no adverse health effects with gadolinium retention in the brain, but that Committee recommended suspending the marketing authorization of certain linear GBCAs because they cause a greater retention of gadolinium in the brain compared to macrocyclic GBCAs. The Committee’s recommendation is currently undergoing an appeal, which will be further reviewed by the PRAC and subsequently by the EMA’s Committee for Medicinal Products for Human Use.18
We are continuing to assess the safety of GBCAs. FDA’s National Center for Toxicological Research (NCTR) is conducting a study on brain retention of GBCAs in rats. Other research is also being conducted about how gadolinium is retained in the body. We will update the public when new information becomes available and we plan to have a public meeting to discuss this issue in the future.
We urge patients and health care professionals to report side effects involving GBCAs or other medicines to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.
The list of approved GBCAs and References included with this FDA Communication can be found here: https://www.fda.gov/Drugs/DrugSafety/ucm559007.htm
The link to MedWatch can be found on the Contact FDA page.
Animal studies have shown that D-glucose is a potential biodegradable MRI contrast agent for imaging glucose uptake in tumors. According to findings reported by Xu et al in “Dynamic Glucose-Enhanced (DGE) MRI: Translation to Human Scanning and First Results in Glioma Patients”, dynamic glucose-enhanced (DGE) imaging is feasible in humans. Chemical exchange saturation transfer (CEST) MRI was used to image dynamic signal changes in the human brain at 7 Tesla (7T) during and after infusion of D-glucose (sugar).
DGE image data from 4 normal volunteers and 3 glioma patients showed strong signal enhancement in blood vessels, while the enhancement varied spatially over the tumor. The authors noted that the areas of enhancement differed spatially between DGE and conventional Gd-enhanced imaging, suggesting complementary image information content for these two types of agents.
The researchers concluded that it was possible to detect water signal changes in the human brain induced by infusion of D-glucose. They said that the signal changes are due to glucose uptake in vessels, the brain and tumor tissue areas, and are related to the kinetics of delivery, transport and metabolism of D-glucose. They noted that an interesting finding is that different tumor areas showed varying times of enhancement, which suggests that the dynamic time curves may contain information about blood-brain barrier (BBB) permeability.
According to the study authors, a larger human study is needed, and for DGE to become relevant clinically, it would have to be possible at 3 Tesla and preferably also at 1.5 Tesla.
Why this is important for patients – (more…)
A recent study by Murata et al, “Macrocyclic and Other Non-Group 1 Gadolinium Contrast Agents Deposit Low Levels of Gadolinium in Brain and Bone Tissue: Preliminary Results from 9 Patients with Normal Renal Function”, adds to the mounting evidence of gadolinium deposition and retention in patients with normal renal function. The study, published online ahead of print in Investigative Radiology, found that “Gadolinium deposition in normal brain and bone tissue occurs with macrocyclic and linear protein interacting agents in patients with normal renal function”. The authors noted that, “Deposition of Gd in cortical bone occurs at much higher levels compared with brain tissue and shows a notable correlation between the two”.
The linear gadolinium-based contrast agents (GBCAs) most frequently associated with NSF were designated as Group 1 agents by the FDA in 2010. Those agents are gadodiamide (Omniscan), gadoversetamide (OptiMARK), and gadopentetate (Magnevist). The linear protein binding agents include gadobenate dimeglumine (MultiHance), gadoexetate (Eovist), and gadofosveset (Ablavar). (more…)
A recent review article by Ramalho et al summarizes the literature on gadolinium-based contrast agents or GBCAs that are administered for contrast-enhanced MRIs, and it ties together information on agent stability, and animal and human studies. The article, “Gadolinium-Based Contrast Agent Accumulation and Toxicity: An Update”, also emphasizes that the low-stability agents are the ones most often associated with brain deposition of gadolinium that has been reported in the literature since 2014.
Since the article has Open Access at AJNR.org, I will not go into all of the details of it. However, there are some facts contained in the paper that I want to present here that are relevant to why GadoliniumToxicity.com exists. In 2014, Hubbs Grimm and I created this website as a way to alert people to a problem that was not yet recognized by the FDA and medical industry. That problem was gadolinium retention in patients with normal renal function. We knew the facts were in the published literature, but they just had not been seen by the right people yet. Thankfully, that has now begun to change.
Nephrogenic Systemic Fibrosis (NSF)
No review of GBCAs would be complete without some background information on NSF.
In 2006, the association between the administration of GBCAs and the development of Nephrogenic Systemic Fibrosis (NSF) in patients with severe renal disease was reported by Grobner and then by Marckmann et al. NSF predominantly involves the skin, but it is a systemic disease that may also affect other organs such as the lungs, liver, heart, and muscles. The exact pathophysiology of NSF remains unknown, but as the review states, the dissociation of gadolinium ions from their chelating ligands has been accepted as the primary etiology. That is more likely to occur in patients with renal failure than in those with normal renal function since the excretion rate is reduced in those with renal failure. The article indicates that most cases of NSF reported in the literature have been associated with the administration of nonionic, linear gadodiamide (Omniscan, GE Healthcare), nonionic, linear gadoversetamide (OptiMARK, Covidien), and with ionic, linear gadopentetate dimeglumine (Magnevist, Bayer HealthCare Pharmaceuticals).
After limiting the use of GBCAs in patients with renal failure and using more stable GBCAs, there have been no new cases of NSF reported since mid-2009. According to the paper, from 2009 to 2014, confidence in the safety of GBCAs had been largely restored. However, since 2014, numerous studies have been published that reported finding evidence of gadolinium deposition in neural tissues in patients with normal renal function. (more…)