FDA Safety Communication

FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings

Safety Announcement

[12-19-2017] The U.S. Food and Drug Administration (FDA) is requiring a new class warning and other safety measures for all gadolinium-based contrast agents (GBCAs) for magnetic resonance imaging (MRI) concerning gadolinium remaining in patients’ bodies, including the brain, for months to years after receiving these drugs. Gadolinium retention has not been directly linked to adverse health effects in patients with normal kidney function, and we have concluded that the benefit of all approved GBCAs continues to outweigh any potential risks.

However, after additional review and consultation with the Medical Imaging Drugs Advisory Committee, we are requiring several actions to alert health care professionals and patients about gadolinium retention after an MRI using a GBCA, and actions that can help minimize problems. These include requiring a new patient Medication Guide,providing educational information that every patient will be asked to read before receiving a GBCA. We are also requiring manufacturers of GBCAs to conduct human and animal studies to further assess the safety of these contrast agents.

GBCAs are used with medical imaging devices called MRI scanners to examine the body for problems such as cancer, infections, or bleeding. GBCAs contain gadolinium, a heavy metal. These contrast agents are injected into a vein to improve visualization of internal organs, blood vessels, and tissues during an MRI, which helps health care professionals diagnose medical conditions. After being administered, GBCAs are mostly eliminated from the body through the kidneys. However, trace amounts of gadolinium may stay in the body long-term. Many GBCAs have been on the market for more than a decade.

Health care professionals should consider the retention characteristics of each agent when choosing a GBCA for patients who may be at higher risk for gadolinium retention (see Table 1 listing GBCAs). These patients include those requiring multiple lifetime doses, pregnant women, children, and patients with inflammatory conditions. Minimize

This is an update to the FDA Drug Safety Communication: FDA identifies no harmful effects to date with brain retention of gadolinium-based contrast agents for MRIs; review to continue issued on May 22, 2017.

repeated GBCA imaging studies when possible, particularly closely spaced MRI studies. However, do not avoid or defer necessary GBCA MRI scans.

Patients, parents, and caregivers should carefully read the new patient Medication Guide that will be given to you before receiving a GBCA. The Medication Guide explains the risks associated with GBCAs. Also tell your health care professional about all your medical conditions, including:

• If you are pregnant or think you might be pregnant

• The date of your last MRI with gadolinium and if you have had repeat scans with

  gadolinium

• If you have kidney problems

  There are two types of GBCAs based on their chemical structures: linear and macrocyclic (see Table 1 below). Linear GBCAs result in more retention and retention for a longer time than macrocyclic GBCAs. Gadolinium levels remaining in the body are higher after administration of Omniscan (gadodiamide) or OptiMARK (gadoversetamide) than after Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine), or MultiHance (gadobenate dimeglumine). Gadolinium levels in the body are lowest after administration of Dotarem (gadoterate meglumine), Gadavist (gadobutrol), and ProHance (gadoteridol); the gadolinium levels are also similar across these agents.

  Table 1. FDA-Approved GBCAs*

*Linear GBCAs result in more gadolinium retention in the body than macrocyclic GBCAs.†Gadolinium levels remaining in the body are LOWEST and similar after use of these agents.‡Gadolinium levels remaining in the body are HIGHEST after use of these agents.

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. We have also received reports of adverse events involving multiple organ systems in patients with normal kidney function. A causal association between these adverse events and gadolinium retention could not be established.

We are continuing to assess the health effects of gadolinium retention in the body and will update the public when new information becomes available. We are requiring the following specific changes to the labeling of all GBCAs:

• A Warning and Precaution

• Changes related to gadolinium retention in the Adverse Reactions, Pregnancy,Clinical Pharmacology, and Patient Instructions sections

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.