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Gadolinium Based Contrast Agents Used Off-Label in MRAs Pose Even Greater Risk of Causing NSF than if Used in MRIs

Oct 30, 2007 | Parker Waichman Alonso LLP

Gadolinium based contrast agents used during MRIs, are known to be associated with the onset of Nephrogenic Systemic Fibrosis/ Nephrogenic Fibrosing Dermopathy (NSF/NSD) in patients with pre-existing kidney disease.   But the use of gadolinium in a procedure call Magnetic Resonance Angiography (MRA) could put these patients at an even greater risk of developing NSF/NSD, because these procedures often use far more gadolinium than a typical MRI.  The use of gadolinium contrast agents in MRAs is a growing practice, even though the Food Drug Administration (FDA) never approved gadolinium for MRAs.

An MRA is a variation of a traditional MRI that is used to provide pictures of blood vessels inside the body. In many cases, an MRA can provide information that cannot be obtained from an X-ray, ultrasound, or computed tomography (CT) scan.  An MRA is often used to detect aneurysms, blood clots or narrowing caused by plaque buildup in the blood vessels leading to the brain, and it is also used to find similar narrowing in the vessels leading to the lungs, kidneys and legs.

Currently, five gadolinium based contrast agents are approved for use by the FDA.  These are Omniscan, Optimark, Magnevist, Multihance and Prohance.  Gadolinium contrast agents are used during MRAs for the same reason they are used in MRIs, to help differentiate between normal and abnormal tissue.  The gadolinium based contrast agent is injected into the bloodstream right before an individual undergoes an MRA. However, in order to be effective in an MRA,  the gadolinium contrast agent must be administered at three times the approved dose.  What’s more, this constitutes an off-label use of gadolinium based contrast agents – that is these agents were never approved by the FDA to be used with MRAs. 

In 2006, evidence began to emerge that gadolinium based MRI contrast agents were linked to the development of NSF/NSD.   NSF/NSD is a debilitating disease that affects people with pre-existing kidney disease.   The first case of NSF/NSD was reported in 1997, and it wasn’t mentioned in medical literature until 2000.   NSF/NSD leads to excessive formation of connective tissue in the skin and internal organs.  It is characterized by high blood pressure, burning, itching, swelling and hardening of the skin. Other symptoms include red or dark patches on the skin; pain deep in the hip bones or ribs and muscle weakness. NSF/NSD can progress to the point of causing severe stiffness in joints, and it can lead to death. Unfortunately, for many patients with NSF/NSD, the only way to improve kidney function is with a transplant.

In 2006, Dutch researchers discovered that the use of gadolinium based contrast agents had a direct correlation to the development of NSF/NSD in patients with pre-existing kidney problems. Following the 2006 discovery, the FDA warned healthcare professionals that gadolinium based agents had been tied to multiple cases of NSF/NSD. As more studies reinforced the theory that gadolinium based contrast agents were linked to NSF/NSD, the FDA decided to add a black box warning to the labels of these agents in 2007.  The FDA also reiterated that gadolinium based contrast agents were not approved for use with MRAs, and the high doses of gadolinium based contrast agents needed in these procedures were also well above the levels approved by the agency.

Off-label use is not illegal, as doctors are free to prescribed approved medications in anyway they see fit.  However, off-label marketing of a drug by its manufacturer is illegal.   So far, the FDA has not investigated the five manufacturers of gadolinium based contrast MRI agents to see if they are actively marketing these products for use in MRAs.