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The U.S. Food and Drug Administration (FDA) has asked manufacturers to include a new boxed warning on the product labeling of all gadolinium-based contrast agents which are used to enhance the quality of magnetic resonance imaging (MRI). The requested warning would state that patients with severe kidney insufficiency who receive gadolinium-based agents are at risk for developing a debilitating, and a potentially fatal disease known as nephrogenic systemic fibrosis (NSF). In addition, it would state that patients just before or just after liver transplantation, or those with chronic liver disease, are also at risk for developing NSF if they are experiencing kidney insufficiency of any severity. “FDA has been carefully monitoring potential safety signals related to these contrast agents after receiving reports about the risk of this potentially life-threatening disease,” said Steven Galson, M.D., M.P.H., director of FDA’s Center for Drug Evaluation and Research. “This latest action demonstrates FDA’s continuing vigilance about ensuring the safety of drug products once they enter the marketplace.” Patients with NSF develop thickening of the skin and connective tissues that inhibits their ability to move and may result in broken bones. Other organs are at risk of thickening as well. The cause of NSF is not known and there is no consistently effective treatment of this condition. FDA first notified health care professionals and the public about the gadolinium-related risks for NSF in June 2006 . Information on the risks was updated in December. Gadolinium-based contrast agents are commonly used to improve the visibility of internal structures when patients undergo an MRI. Five gadolinium-based contrast agents have been approved for use in the United States: Magnevist (gadopentetate dimeglumine), Ominiscan (gadodiamide); OptiMARK (gadoversetamide); MultiHance;(gadobenate dimeglumine);and Prohance (gadoteridol). Reports have identified the development of NSF following single and multiple administrations of the gadolinium-based contrast agents.
The reports have not always identified a specific agent. Omniscan was the most commonly reported agent, when a specific agent was identified, followed by Magnevist and OptiMARK. NSF also has developed after the sequential administration of Omniscan and MultiHance and Omniscan and ProHance. Because reports incompletely describe exposure to gadolinium-based contrast agents, it is not possible to know if the extent of risks for developing NSF is the same for all agents. Patients should be screened for kidney problems prior to receiving one of these imaging agents. The recommended dose should not be exceeded and enough time should elapse to ensure that a dose has been eliminated from the body before the agent is used again. There have been no reports of NSF among patients with normal kidney function or those with mild-to-moderate kidney insufficiency. Bayer Schering Pharma, Berlin, Germany, manufactures Magnevist; GE Healthcare, Chalfont St. Giles, U.K., is the maker of Omniscan; OptiMARK is manufactured by Mallinckrodt, Inc., Hazelwood, Mo.; and ProHance and Multihance are made by Bracco Diagnostics Inc., Princeton, N.J.
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Nephrogenic Systemic Fibrosis/ Nephrogenic Fibrosing Dermopathy (NSF/NFD)
Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance)
FDA ALERT [6/2006, updated 12/2006 and 5/23/2007]: This updated Alert highlights FDA’s request for addition of a boxed warning and new warnings about risk of nephrogenic systemic fibrosis (NSF) to the full prescribing information for all gadolinium-based contrast agents (GBCAs) (Magnevist, MultiHance, Omniscan, OptiMARK, ProHance). This new labeling highlights and describes the risk for NSF following exposure to a GBCA in patients with acute or chronic severe renal insufficiency (a glomerular filtration rate less than 30 mL/min/1.73m2) and patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the peri-operative liver transplantation period. In these patients, avoid the use of a GBCA unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging. NSF may result in fatal or debilitating systemic fibrosis. Requested changes to GBCA product labeling are summarized below. This information reflects FDA’s current analysis of data available to FDA concerning this drug.
FDA intends to update this sheet when additional information or analyses become available.
FDA has requested manufacturers of all gadolinium-based contrast agents (GBCAs) to add a new Boxed Warning and new Warnings about Nephrogenic Systemic Fibrosis (NSF). A new Boxed Warning and new Warnings section describe NSF, populations at risk for NSF, and advise on screening procedures, dosing and other considerations:
Boxed Warning: Exposure to GBCAs increases the risk for NSF in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min/1.73m2), or acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. NSF is a debilitating and sometimes fatal disease affecting the skin, muscle, and internal organs. Avoid use of GBCAs unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a GBCA, do not exceed the dose recommended in product labeling. Allow sufficient time for elimination of the GBCA prior to any readministration. Additional New Warnings: Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA. For patients receiving hemodialysis, healthcare professionals may consider prompt hemodialysis following GBCA administration in order to enhance the contrast agent’s elimination. However, it is unknown if hemodialysis prevents NSF. Determine the renal function of patients by obtaining a medical history or conducting laboratory tests that measure renal function prior to using a GBCA. The risk, if any, for developing NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown. Post-marketing reports have identified the development of NSF following single and multiple administrations of GBCAs. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was Omniscan, followed by Magnevist and OptiMARK. NSF has also developed following the sequential administration of Omniscan and MultiHance and Omniscan and ProHance. The distribution of the number of reports for the individual GBCAs may relate to multiple factors, including more limited use of some GBCAs, under-reporting of NSF, characteristics of the agent and a lack of patients’ complete GBCA exposure history. Recommendations and Considerations for Healthcare Professionals: Become familiar with the patient populations who are at known risk for NSF. To date, NSF has only been identified in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min/1.73m2); acute renal dysfunction due to the hepato-renal syndrome or in the perioperative liver transplantation period. Avoid using a GBCA in patients with known risks for developing NSF unless the diagnostic information is essential and can not be obtained with non-contrast enhanced MRI or other diagnostic procedures. Prior to administering a GBCA, evaluate patients for renal dysfunction by assessing their renal function, either by obtaining a medical history or conducting laboratory tests that measure renal function. When administering a GBCA, do not exceed the recommended GBCA dose in product labeling and allow a sufficient period of time for elimination of the agent from the body prior to any GBCA readministration. The elimination characteristics of each GBCA are described in the product label for each GBCA. For patients receiving hemodialysis, consider prompt hemodialysis after administration of a GBCA. Published data indicate that hemodialysis enhances GABA elimination. From the first to the third hemodialysis session, reported average GBCA clearance rates were 78%, 96%, and 99%, respectively.1 Whether hemodialysis prevents NSF is unknown. Report possible cases of NSF to the FDA through the FDA’s MedWatch program (see reporting information at the bottom of this page). Information for the patient: Physicians who are considering a GBCA for use in a patient who is at risk for NSF should discuss the following with the patient: The possibility of developing NSF, a debilitating and potentially fatal disease that involves the skin, muscle and internal organs. The signs and symptoms of NSF, which include: For the skin—burning or itching, reddened or darkened patches; and/or skin swelling, hardening and/or tightening For the eyes—yellow raised spots on the whites of the eyes For the bones, joints and muscles—joint stiffness; limited range of motion in the arms, hands, legs, or feet; pain deep in the hip bone or ribs; and/or muscle weakness If the patient is receiving hemodialysis: Prompt hemodialysis immediately after administering a GBCA hastens its elimination. However, whether hemodialysis prevents or reduces the risk of NSF is unknown. After receiving a GBCA, those patients known to be at risk for NSF require clinical follow-up and long term monitoring for the disease. Background Information and Data First identified in 1997, NSF has been reported only in patients with acute or chronic severe renal insufficiency (glomerular filtration rate less than 30 mL/min/1.73m2) or patients with renal dysfunction due to the hepato-renal syndrome or in the perioperative liver transplantation period. Patients with this condition develop fibrosis of the skin and connective tissues throughout their body. The skin thickening may inhibit flexion and extension of joints resulting in contractures. In addition, patients may develop widespread fibrosis of other organs. A skin biopsy is necessary to confirm the diagnosis. The condition may be debilitating or cause death. Its cause is unknown and there is no consistently successful treatment. Five GBCAs (Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance) are approved in the U.S. for magnetic resonance imaging (MRI). The GBCAs are sometimes used for MRA (magnetic resonance angiography) although none are FDA-approved for MRA. The administered dose of the contrast with magnetic resonance angiography (MRA) may be higher (up to three times) than the approved dose for MRI. NSF has been reported following administration of all five FDA approved gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance). However, some adverse event reports of NSF do not include complete information on patients’ GBCA exposure history. Also, reports indicate that some patients received more than one GBCA prior to a NSF diagnosis. The lack of complete information of GBCA exposure, exposure to multiple GBCAs, along with similarities among all these contrast agents, make it impossible at present to definitively determine whether the extent of risks for developing NSF are the same for all the GBCAs. In June 2006, FDA first notified healthcare professionals and the public about the risk of NSF following exposure to GBCAs after receiving reports of 25 patients with NSF from the Danish Health Authority. FDA issued additional information to healthcare professionals and the public in December 2006. FDA review of spontaneously submitted post-marketing reports, sponsor-supplied information and the published literature identifies the following: FDA has received reports of patients who developed NSF after exposure to Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance, unspecified GBCA, and multiple GBCAs (following multiple GBCA enhanced MRI scans). Among the reports that included renal status information, all patients had acute or chronic severe renal insufficiency, renal dysfunction due to the hepato-renal syndrome or renal dysfunction in the perioperative liver transplantation period. The vast majority of patients were receiving hemodialysis. To date, there has not been a report of NSF in a patient with normal renal function or mild to moderate renal insufficiency following GBCA exposure. The reported time between receiving a GBCA and subsequent diagnosis of NSF diagnosis is highly variable. Reported times range between days to many months. FDA has received reports of patients who died from complications related to NSF. FDA has requested the manufacturers of the GBCAs to revise the product labels as soon as possible to include a new boxed warning and new Warnings section that describes the risk of NSF. References 1 Okada S et al. Safety of gadolinium contrast agent in hemodialysis patients. Acta Radiol 2001; 42(3): 399-341.
Since December 2006, FDA has continued to investigate reports of nephrogenic systemic fibrosis (NSF) in patients who received gadolinium-based contrast agents (GBCAs) to help define risk factors for NSF. In addition, the FDA has requested the manufacturers of all five GBCAs (Magnevist, MultiHance, Omniscan, OptiMARK and ProHance) to add a new boxed warning and a new Warnings section to their labels to describe the risk of developing NSF.
Gadolinium is a paramagnetic metal ion.
Paramagnetic ions, such as gadolinium, move differently within a magnetic field. This trait makes gadolinium useful for magnetic resonance imaging (MRI). GBCAs are manufactured by a chelating process, a procedure in which large organic molecules form a stable complex around the gadolinium. The chelate reduces the chances of toxicity that could result from exposure to gadolinium. This stable complex is eliminated predominantly via the kidneys. GBCAs are approved by FDA for use with MRI as a contrast agent to provide an improved image of body organs and tissues. GBCAs are also used for magnetic resonance angiography (MRA), an imaging procedure used to evaluate blood vessels. FDA has not approved GBCAs for use in MRA.
MRA is a special type of MRI used to study blood vessels. MRA aids the detection of heart disorders, stroke, and vascular diseases.
4. Can an MRI and MRA be performed without gadolinium-based contrast? Yes, MRI and MRA can be performed without contrast. MRI with GBCAs provides additional diagnostic information as compared to MRI without contrast. Although GBCAs are not FDA-approved for MRA, some radiologists believe that these agents help provide detailed images of blood vessels.
Yes. However, the two other approved MRI contrast agents, Feridex, I.V. (an iron-containing injectable solution) and Teslascan (a manganese-containing injectable solution) are FDA-approved only for the evaluation of lesions of the liver. Imaging contrast agents, such as iodinated contrast agents are used in Computed Tomography, plain X-ray and X-ray angiography. However, these iodinated contrast agents require X-ray imaging rather than MRI. These agents also have serious risks such as anaphylaxis (a severe and life-threatening allergic reaction) and kidney damage.
At this time, only certain patients who receive GBCAs appear to be at an increased risk for developing a serious systemic fibrosing disease, NSF. The patients at risk are those with acute or chronic severe renal (kidney) insufficiency (glomerular filtration rate < 30 mL/min/1.73m2); or renal dysfunction due to the hepato-renal syndrome or in the perioperative liver transplantation period. In the hepato-renal syndrome or in the perioperative liver transplantation period, the risk applies to any severity of renal dysfunction. A possible association between NSF and GBCAs was first reported in a May 29, 2006, press release from the Danish Medicines Agency (DMA) and the April 2006 report by Grobner et al in Nephrology, Dialysis and Transplantation (2006) Vol 21 (4):1104-1108 and following erratum (2006) 21(6): 1745. Recent publications have provided additional important information implicating a role for GBCAs in the development of NSF among some patients. Researchers have found gadolinium in the tissue of patients with NSF (High et al, J Am Acad Dermatol 2007; 56 (1): 21-26). Also, a retrospective study with Omniscan in about 370 patients with severe renal insufficiency estimated the risk of NSF to be 4% (Marckmann et al, J Am Soc Nephrol 2006; 17: 2359-2362). A case-control study of the occurrence of nephrogenic fibrosing dermopathy (NFD) indicated that exposure to GBCA was independently associated with NFD (MMWR 2007; 56(07):137-141). Together, accumulating data indicate that GBCAs increase the risk for the development of NSF among patients with severe renal insufficiency or renal dysfunction due to the hepato-renal syndrome or in the perioperative liver transplantation period.
The December information was based upon reports of NSF among patients with purportedly moderate renal insufficiency. Since issuing the information in December 2006, FDA has received new information regarding these patients. Additional details have clarified that the patients actually were in acute renal failure at the time they received a GBCA. Considering this clarification, FDA has not received reports of NSF among patients with normal renal function or moderate renal insufficiency.
NSF was first described in the medical literature in 2000. The first case of NSF was identified in 1997. The cause of NSF is unknown but it has been reported only in patients who have severe kidney disease. NSF causes fibrosis of the skin and connective tissues throughout the body. Patients develop skin thickening that may prevent bending and extending joints, resulting in decreased mobility of joints. NSF usually starts in the lower extremities. Fibrosis can also develop in the diaphragm, muscles in the thigh and lower abdomen, and lung vessels. Over time, NSF becomes worse and can cause death.
There is no known treatment for NSF. Improved renal function (spontaneous or via renal transplantation) appears to slow or arrest NSF and may even result in a gradual reversal of NSF. Other treatments are being tested.
There are five FDA approved GBCAs (Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance).
NSF has been reported following administration of all five FDA approved gadolinium-based contrast agents (Magnevist, MultiHance, Omniscan, OptiMARK, and ProHance). However, some adverse event reports of NSF do not include complete information on patients’ GBCA exposure history. Also, some reports indicate that some patients received more than one GBCA prior to NSF diagnosis. The lack of complete information of GBCA exposure, exposure to multiple GBCAs, along with similarities in structure and activity of all these contrast agents, make it impossible at present to definitively determine whether the extent of risks for developing NSF is shared by all GBCAs or vary for some of them. Therefore, FDA considers that NSF may occur following the administration of any of the approved GBCAs to certain patients.
Whether the GBCAs are the only agents or conditions that may be associated with NSF in patients with renal disease is unknown. The conclusions that can be drawn from the NSF reports are limited. However, the reports FDA has received, the published report of gadolinium deposits in the skin of patients with NSF/NFD, and other published reports suggest that GBCAs play a role in the development of NSF in patients with acute or chronic severe kidney insufficiency or kidney dysfunction due to the hepato-renal syndrome or in the perioperative liver transplantation period.
FDA has requested that the manufacturers of the 5 GBCAs include a new Boxed Warning and new Warnings section in the labels that describe the risks of developing NSF. Additionally, FDA has requested that all manufacturers prospectively collect data on patients with varying degrees of renal insufficiency who are exposed to GBCA to more accurately estimate the magnitude of the risk for NSF for patients with kidney disease. FDA will continue to evaluate new reports of NSF and may request additional studies and/or labeling changes.
The five U.S. approved GBCAs were approved between 1988 and 2004. In the combined pre-marketing studies for these approved GBCAs, over 3000 patients were studied. The most common serious side effect from GBCAs is an allergic reaction that is usually mild but is occasionally severe and even results in fatalities. Some patients develop skin conditions, such as rash, sweating, itching, hives, and facial swelling. GBCAs can be very irritating to the veins into which they are injected, causing irritation of blood vessels and skin and the formation of blood clots. Very few patients with severely compromised kidney function or those on dialysis have been studied in clinical trials. The labels for GBCAs caution that the risk of toxic reactions may be greater in patients with impaired kidney function because gadolinium is mostly excreted by the kidney.
If you have severe renal insufficiency (severe kidney disease) and a physician has requested an MRI or MRA study with a contrast agent, ask if the use of the contrast agent is essential. In some situations, an acceptable study can be obtained without the use of contrast. If a GBCA is essential, you and your physician should consider that the dose of the contrast agent should not exceed that recommended in the product’s label and that a repeat administration of the contrast agent should not be performed until enough time has passed to allow for the preceding contrast agent to be eliminated from your body. If administration of a GBCA is essential and you are already receiving hemodialysis, your physician may recommend the performance of hemodialysis shortly following administration of a GBCA. This hemodialysis may help eliminate the GBCA from your body. Whether hemodialysis will help prevent NSF is unknown. Contact your doctor right away after receiving a GBCA if you get any of these conditions that may indicate the development of NSF: Skin and eyes Swelling, hardening and tightening of your skin Reddened or darkened patches on the skin Burning or itching of your skin Yellow raised spots on the whites of your eyes Bones and muscles Stiffness in your joints; problems moving or straightening arms, hands, legs, or feet Pain deep in your hip bones or ribs Muscle weakness 17. What should healthcare providers do in response to this new information? Physicians should consider the risks and benefits of using GBCAs in patients with acute or chronic severe renal insufficiency (glomerular filtration rate http://www.pathmax.com/dermweb/.
If you or a loved one has had an MRI or MRA scan and been diagnosed with Nephrogenic Systemic Fibrosis/ Nephrogenic Fibrosing Dermopathy (NSF/NFD) then you should call us toll free now at 1-866-374-0338 because you may be entitled to medical monitoring and compensation from the manufacturer.
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