CRDAC B1 06 GE Omniscan

Omniscan Advisory Meeting Briefing Document GE Healthcare
Version 1.0 November 3, 2009
Omniscan Safety Review Advisory Meeting Briefing Document
AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION
GE Healthcare Inc. 101 Carnegie Center Princeton, NJ, 08540-6231
1 2 3 4
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.................................5 INTRODUCTION .......................................................................................................... 7 EXECUTIVE SUMMARY ............................................................................................ 9 OMNISCAN HISTORY, UTILIZATION, AND SAFETY......................................... 11 4.1 4.2 4.3 4.4 NDA Approval..................................................................................................11 Drug Distribution.............................................................................................. 11 Drug Utilization ................................................................................................ 13 Overall Safety of Omniscan.............................................................................. 14 4.4.1 4.4.2 4.4.3 4.4.4 Immune system reactions ............................................................... 17 Renal reactions................................................................................ 17 Nervous system reactions ............................................................... 18 Fatalities.......................................................................................... 18
NEPHROGENIC SYSTEMIC FIBROSIS................................................................... 19 5.1 5.2 Description of NSF ........................................................................................... 19 5.1.1 General 5.2.1 5.2.2 5.3 Additional Risk factors ................................................................... 20 ........................................................................................................ 21 Epidemiology.................................................................................. 21 Incidence, prevalence, mortality and demographic profile of the population at risk of NSF................................................................ 22 Clustering of Cases ......................................................................... 30 Characteristics of Reported Omniscan-Associated NSF Cases...... 32 ........................................................................................................ 36
Global Postmarketing Reports of NSF Associated with Omniscan ................. 27 5.3.1 5.3.2
5.4 5.5 6 7
Type of renal failure and stage of chronic renal failure.................................... 34 Trending
ACTIONS TAKEN TO ENSURE PATIENT SAFETY..............................................39 STUDIES OF NSF ....................................................................................................... 41 7.1 7.2 7.3 7.4 Investigations in Human Bone.......................................................................... 41 Investigations of Human Skin .......................................................................... 41 Investigations of Human Serum ....................................................................... 42 In Vitro Studies................................................................................................. 42
7.5 7.6 7.7 8
GE Healthcare Nonclinical Studies .................................................................. 42 Published Clinical Study................................................................................... 43 GE Healthcare Post-Marketing Clinical Trials................................................. 43
ASSESSMENT OF DIFFERENTIAL RISK ...............................................................46 8.1 8.2 8.3 GBCA Physical Chemistry ............................................................................... 46 Utilization Rates ............................................................................................... 46 Other Safety Considerations Among GBCAs .................................................. 47
9 10
CONCLUSIONS ..........................................................................................................49 REFERENCE LIST ...................................................................................................... 51
List of Figures Figure 1 Figure 2 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Figure 9 Distribution volume relative to NSF cases reported...............................................13 Omniscan Post-Marketing Safety Profile by Body System*.................................. 14 NSF reports associated with Omniscan. Size of last contrast dose ................... 29 Omniscan-related NSF in 351 cases reported by HCPs and in 273 cases reported by non-HCPs by country (as of data lock point June 30, 2009) ............................. 30 Omniscan-related NSF (624 cases) by country (data lock point June 30, 2009) ... 31 NSF Reports Associated with Omniscan by Stage of Kidney Disease Stage (HCP and non-HCP Sources) ................................................................................. 35 Date of onset - NSF cases associated with Omniscan ............................................ 37 Volume sold relative to NSF cases ......................................................................... 38
Figure 3 The characteristic appearance of NSF....................................................................... 19
Figure 10 Schematic for release of profibrotic preceding formation of tissue retained insoluble Gd3+........................................................................................................ 85 Figure 11 Schematic of the proposed mechanism ................................................................... 86 List of Tables Table 1 Table 2 Table 3 Estimated number of units distributed in countries reporting NSF (January 1998 to July 2009) ........................................................................................................... 12 Adverse drug reactions and serious adverse drug reactions following administration of Omniscan.................................................................................... 15 Adverse drug reactions and serious adverse drug reactions following administration of Omniscan (Category Other in Table 2) ...................................... 16
Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 11
Adverse drug reactions and serious adverse drug reactions of the gastrointestinal tract following administration of Omniscan ........................................................... 16 Adverse drug reactions and serious adverse drug reactions of skin and subcutaneous tissue following administration of Omniscan .................................. 16 Adverse drug reactions and serious adverse drug reactions following administration of Omniscan.................................................................................... 17 Adverse drug reactions and serious adverse drug reactions of the renal and urinary system following administration of Omniscan .......................................... 17 Adverse drug reactions and serious adverse drug reactions of the nervous system following administration of Omniscan ................................................................... 18 Demographic profile of the population at risk of NSF .......................................... 22 Number of Reported NSF Cases Deemed Related to Various GBCAs ................ 27
Table 10 Data from published epidemiologic studies on NSF .............................................. 23 Table 12 Details of NSF cases associated with Omniscan .................................................... 32 Table 13 Reasons that Sites Declined Participation in Study GE-141-071 Following Initial Contact.................................................................................................................... 44 Table 14 Omniscan Safety Study (GE-041-075) Summary October 2009............................ 45 Table 15 Adverse Reactions .................................................................................................. 48 Appendices APPENDIX A APPENDIX B APPENDIX C APPENDIX D APPENDIX E APPENDIX F APPENDIX G Abstracts Nonclinical Studies Animal Modes (in vivo studies) Proposed alternative hypothesis for the mechanism of NSF Table of Nonclinical Trials Letter to Healthcare Professionals Omniscan Package Insert
1
ACR AE ARF BUN CCLx CI CIN CKD CM CXCL10 eGFR ELISA EPO ESRD FDA GBCA(s) Gd GFR HCP(s) HD ICP-AES
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

American College of Radiology Adverse Event Acute Renal Failure Blood Urea Nitrogen Chemokine (C-C motif) ligands x Confidence Interval Contrast Induced Nephropathy Chronic Kidney Disease Contrast Media (or Medium) Chemokine (C-X-C motif) ligand 10 Estimated Glomerular Filtration Rate Enzyme Linked Immunosorbent Assay Erythropoietin End Stage Renal Disease US Food and Drug Administration Gadolinium-Based Contrast Agent(s) Gadolinium Glomerular Filtration Rate Health Care Professional(s) Hemodialysis Inductively Coupled Plasma Atomic Emission Spectroscopy Inductively Coupled Plasma Sector Field Mass Spectrometry Institutional Review Board
Available for public disclosure without redaction
ICP-SF-MS IRB
MDRD MMP-1 MRA MRI NDA NFD NSF OR PCA QWBA RI SCr SEM SIRF sNDA TEM TIMP-1 TLR WIRB
Modification of Diet in Renal Disease Matrix Metalloproteinase-1 Magnetic Resonance Angiography Magnetic Resonance Imaging New Drug Application Nephrogenic Fibrosing Dermopathy Nephrogenic Systemic Fibrosis Odds Ratio Posterior Cerebral Artery Quantitative Whole Body Autoradiography Renal Insufficiency Serum Creatinine Scanning Electron Microscopy Severely Impaired Renal Function Supplemental New Drug Application Transmission Electron Microscopy Tissue Inhibitor of Matrix Metalloproteinase-1 Toll-Like Receptor Western Institutional Review Board
INTRODUCTION
Gadolinium-based contrast agents (GBCAs) are medical imaging drugs used to enhance magnetic resonance imaging (MRI) of the general body, central nervous system (CNS) and vasculature. FDA has approved NDAs for seven GBCAs, although not all are presently available on the US market. Several other GBCAs have been approved by non-US regulatory authorities and are available in those markets. Gadolinium, which is key to GBCA enhancement of MRI, is chelated within the imaging agent molecules to lessen toxicity to this lanthanide metal. Chelation both shields the body from the metal ion and promotes the GBCAs elimination. Structurally, there are two types of chelated molecules among the GBCAs, linear and macrocyclic. Of the GBCAs approved in the US market, Omniscan, Magnevist, OptiMARK, MultiHance, Eovist, and Ablavar are linear and ProHance (as well as Dotarem, which is not approved in the US) is macrocyclic. As a class, these agents are well tolerated and have been used widely throughout the world. Since 2006, however, a new and potentially serious adverse condition, seen in patients primarily with severe renal insufficiency, has been reported spontaneously in association with almost all members of the class. Global regulatory authorities and drug manufacturers have conducted investigations and disseminated a variety of communications to healthcare professionals concerning the class-related labeling actions restricting the use of GBCAs in the at-risk population and emphasizing use of appropriate doses as reflected in approved prescribing information. In 2007 some authorities (e.g., FDA) took a uniform class labeling action while other authorities (e.g., EMEA) have taken a differential approach to class-labeling these GBCAs. Together these actions appear to have contributed to a marked reduction (i.e., virtual elimination) in reports of new cases of NSF globally. To better understand the association between NSF and GBCAs, the FDA has required individual NDA post-marketing commitments for clinical trials with the agents approved in the US. At this time two major regulatory authorities (FDA and EMEA) are further evaluating the safe use of these agents. As part of this re-evaluation, on December 8, 2009 FDA will convene a meeting of the Cardio-Renal Advisory Committee and Drug Safety/Risk Management Advisory Committee for a discussion of the safety of the GBCAs that are approved for the US market. This background material from GE Healthcare is intended to provide the committee members with the sponsors assessment of the overall safety of Omniscan (gadodiamide) Injection for Intravenous Use (NDA 20-123). It will also provide an overview of what GE Healthcare has learned regarding the use of Omniscan and other GBCAs in the development of NSF in patients with renal impairment.
The background material is organized as a core document following this introduction and is accompanied by appendices containing additional information referenced within the core document which members of the advisory committee may wish to consult. To facilitate navigation and review, the electronic version of the material contains hyperlinks within the core document, as well as between it and the appendices.
EXECUTIVE SUMMARY
GE Healthcares Omniscan (gadodiamide) Injection for Intravenous Use (NDA 20-123), was approved in 1993, and is the second most widely prescribed GBCA (over 48 million doses distributed). In clinical studies with Omniscan the most frequent adverse reactions were nausea, headache, and dizziness each occurring in 3% or less of exposed patients. Based upon the GE Healthcare Pharmacovigilance (PV) database, the safety profile of Omniscan is characterized mainly by hypersensitivity reactions (31% of all AEs reported), followed by gastrointestinal reactions (24%; nausea, vomiting and taste alteration), skin reactions (16%; mainly NSF), and reactions from the nervous system (11%). Over 85% of immune system reactions are non-serious reactions (e.g., rashes and urticarial reactions) with some severe and life-threatening anaphylactic reactions or shock. Only one case of a fatal hypersensitivity reaction has been reported since launch of the product in 1993. Nephrogenic Systemic Fibrosis (NSF) is a rare, but potentially serious, acquired systemic condition reported in association with the administration of gadolinium-based contrast agents (GBCAs). This association has been reported primarily in patients with significant renal impairment, typically severe renal insufficiency associated with end-stage kidney disease. NSF was first described in the medical literature in 2000; however, it was not until 2006 the GE Healthcare received the first adverse event reports associating the condition with the administration of Omniscan. Class labeling and contraindications for use in this population have contributed to a dramatic reduction in the occurrence of NSF in patients receiving GBCAs. The occurrence of NSF is one exception to the overall safety and tolerability of GBCAs. GBCAs, including Omniscan, are well tolerated among the greater than 99% of patients in which they are used. To date, NSF has been reported predominantly in patients with severe renal insufficiency (whether chronic or as a result of acute kidney injury), particularly in patients with end stage renal disease (ESRD). At present, there is no evidence that patients without renal impairment, or with mild renal insufficiency, are at risk of developing this disease; however, there have been reports of NSF that were not associated with GBCAs. One factor that may increase the risk of NSF in patients with renal failure is the administration of doses of GBCAs at the high end or above those identified in approved prescribing information. Spontaneous global case reports of NSF have been associated with almost all marketed GBCAs. In its communications to Healthcare Professionals (HCPs) about the association of NSF with GBCAs, GE Healthcare actively solicited the reporting of AEs potentially involving NSF following exposure to Omniscan and has received the largest number of reports, 624 to date. In June and December 2006 GE Healthcare and FDA delivered parallel communications to healthcare professionals about reports of NSF in relation to use of GBCAs, including Omniscan, in patients with chronic, severely-impaired renal function and acute renal failure, and in those with liver disease. In 2007, global health authorities required label changes for all GBCAs warning of the risk of NSF in patients with severe renal impairment. Among reports for which the onset of NSF is
known, there have been no plausible cases associated with Omniscan with a documented date of onset later than September 2007. Communications and labeling revisions by global regulatory agencies and manufacturers of the risk of NSF and precautions in the use of GBCAs in patients with renal failure appear to have contributed to a marked reduction (i.e., virtual elimination) in reports of NSF. At this time there is no evidence to indicate that additional precautions or differential labeling are necessary to improve patient safety for the use of GBCAs. There are some cases reported in the literature describing NSF in patients with no history of GBCA exposure, supporting the view that NSF is a complex disease with a number of contributing factors. Although an association with exposure to free or dissociated gadolinium has been posited, GE Healthcare believes that there is no direct evidence linking the stability of GBCAs to the development of NSF. Predictions of in vivo stability and toxicity of gadolinium chelates based on an in vitro measure such as thermodynamic stability do not consistently explain the relative numbers and clustering of NSF case reports for the various GBCAs. Over the past three years GE Healthcare has conducted numerous studies to try and understand the underlying mechanisms of this potentially serious condition. Even after conducting multiple well-designed nonclinical studies, it has proven challenging to clearly differentiate factors that relate to or predict NSF outcome based on in vitro and in vivo data. A GE Healthcare Postmarketing commitment clinical trial, GE-041-075, is currently under way in patients with renal impairment to assess the magnitude of the risk of NSF in this patient population. Other than differences in the number of spontaneous reports, there is no clear evidence to indicate that any one GBCA is more or less safe than any other with respect to NSF. The number of reports is confounded by multiple factors thus making it challenging to establish any basis to assess differential risk across the class of GBCAs. There are no reasonable head-to-head studies that could be used to establish a regulatory basis for any differentiation. Postmarketing surveillance and structure/physical attribute data do not provide an evidentiary basis to draw significant conclusions regarding a differential risk profile for GBCAs. Overall, since class labeling was implemented in 2007, the safety profile for GBCAs, including Omniscan, has a positive benefit-risk and does not necessitate further labeling actions to assure safe product use. Given product utilization in the marketplace for GBCAs and the adequacy of current labeling (e.g., no new non-confounded cases of NSF associated with Omniscan with an onset after September 2007) it is our strong belief that careful assessment of overall safety (not just limited to NSF) is crucial to the overall assessment of benefit-risk for this class of agents. Additional communications to HCPs may be warranted to remind and assure that product use complies with approved professional product labeling (e.g., approved dose and appropriate use for a given procedure).
10
4 4.1
OMNISCAN HISTORY, UTILIZATION, AND SAFETY NDA Approval
Omniscan (gadodiamide) Injection for Intravenous Use, NDA 20-123, was approved January 8, 1993 for intravenous administration with magnetic resonance imaging in adult patients to provide contrast enhancement in those central nervous system lesions with abnormal vascularity or those thought to cause abnormalities in the blood-brain barrier. Omniscan injection was shown to facilitate visualization of central nervous system lesions including but not limited to tumors. The original approved dosage and administration of Omniscan Injection was 0.1 mmol/kg (bolus intravenous injection). On February 5, 1996 FDA approved a supplemental NDA increasing the maximum dosage to 0.3 mmol/kg for imaging of the central nervous system. Also on February 5, 1996 FDA approved two NDA supplements to support indications for: (1) intravenous administration (0.1 mmol/kg dose) with magnetic resonance imaging of the body in adult patients to facilitate detection or exclusion of space-occupying lesions (including, but not limited to cysts or tumors) inflammation or anatomical abnormalities of the abdomen, retroperitoneal space, breast, pelvis and musculoskeletal system; and (2) 0.1 mmol/kg as a single intravenous bolus injection for magnetic resonance imaging of the central nervous system in infants and children.
4.2
Drug Distribution
Omniscan is approved in more than 90 countries worldwide and it is estimated that approximately 48 million units have been distributed during the period from its first launch in February 1993 to July 2009. Table 1 lists the numbers of units of Omniscan distributed between January 1998 and July 2009 in those countries from which reports of Omniscanassociated NSF have been received.
11
Table 1
Estimated number of units distributed in countries reporting NSF (January 1998 to July 2009)
Country Australia Austria Belgium Brazil Canada Chile Denmark Finland France Germany Greece Japan* The Netherlands Norway Singapore Spain Sweden Switzerland Taiwan United Kingdom USA Number of Units 321 430 418 742 301 511 993 498 575 060 218 772 119 060 65 680 1 419 408 2 743 188 380 122 4 332 267 266 136 256 140 82 170 1 036 440 293 320 349 255 298 390 620 580 21 984 319
Total
37 075 488
*Japan: number of vials sold between January 1998 to January 2009
Figure 1 provides a comparison of distribution and reports of NSF in those countries. The top five countries by gross distribution are the US, Japan, Germany, France and Spain. It should be noted that although product distribution can be tracked it cannot be determined accurately whether a single patient receives more than one unit during a procedure or if a single vial is used for more than one patient as dosing is based on MRI procedure and patient body weight. Even given this perspective, it is interesting to note the significant clustering of events in Denmark which is totally disproportionate relative to Omniscan usage.
12
Figure 1 Distribution volume relative to NSF cases reported

67% 58%
20.00%
Analysis Based Upon US and EU Data Only Volume Data from 2002 - 2007
% of Total in Reported US and EU Countries
% of NSF Cases
15.00%
% of mLs sold
Cases not proportional to volume sold
10.00%
5.00%
0.00%
Sp ai n i um No rw ay
US A
ce
er lan d
do m
SF
ds
en
ia
d F in lan
Un i te dK i ng
Sw i tz
-N
EU
4.3
Drug Utilization
Based on literature publications, it is clear that some clinicians have used higher than labeled doses of Omniscan for off-label MR angiography (MRA) as well as for the possibility to detect more and smaller lesions with MRI. While some patients developing NSF have received Omniscan for approved indications at labeled dosage levels, it has been established that other patients developing NSF have received cumulative, single doses totaling in excess of the approved 0.1-0.3 mmol/kg dose range. Some clinicians perceived GBCAs to be less nephrotoxic than iodinated X-ray contrast media (CM) and advocated their use for X-ray procedures to minimize the risk of developing Contrast Induced Nephropathy (CIN) associated with iodinated CM. Even before NSF became an issue, there were warnings against such practice since image attenuation, similar to that obtained with iodinated CM, required doses of GBCAs that were higher than in approved labeling (Nyman, 2007a and b). At these levels GBCA nephrotoxicity is similar to that of X-ray CM as demonstrated in pig studies by Elmsthl (Elmsthl 2007). Very recently, Hoppe (Hoppe 2009) in a retrospective study identified 27 patients with eGFR <60 mL/min/1.73m2 who had received GBCAs for X-ray examination, one of whom developed NSF.
13
Th
eN
eth
De nm ar k
Ge rm an
Au st r
Fr an
Be lg
Sw ed
er lan
oN
4.4
Overall Safety of Omniscan
In GE Healthcare clinical studies with Omniscan (1160 patients receiving 0.1 to 0.3 mmol/kg), the most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. Reactions identified as serious or life-threatening included: cardiac failure, arrhythmia and myocardial infarction. In pediatric patients in CNS clinical trials with Omniscan the adverse reactions were similar to those in clinical trials with adults. No cases of NSF were reported in clinical studies of Omniscan. In post-marketing experience for Omniscan from the initial (EU) launch in 1993 through 01 July 2009 (48 million doses sold), a total of 4491 suspected adverse reactions in 3507 individual patients were reported to GE Healthcare. The overall adverse reaction rate is very low (estimated to be 0.00009); the rate of serious adverse reactions is estimated to be 0.00002. Details of the worldwide post-marketing safety profile of Omniscan are shown in Figure 2 and Table 2 with details in the text that follows. The listings of events in tables 2 through 8 use a cut-off of 0.5% serious adverse reactions. Figure 2 Omniscan Post-Marketing Safety Profile by Body System*
30
26 Serious (% of total) Nonserious (% of total) 23
25 20 15
14 10
10
5
5
1 1 0
% )
4 1 1 0 1 2 0 1 1 2 0 0 2 1 1
0
% ) Ge nr l (6 % Im ) m un (3 1% ) In v (2 % ) M us c (1 % ) Ne rv (1 1% ) Ps yc h (1 % ) Re na l (1 % ) Re sp (2 % ) Sk in (1 6% ) Va sc (2 % ) % ) Ca rd Ey e Ga st r( 24 (1 (1
NOTE: All reports of NSF are coded as Skin reactions. Included are all MedDRA System Organ Classes with at least one column (serious, non-serious) with a count of greater than 0.5% of in total 4434 reactions. Of these, 1126 (26%) were serious and 3308 (74%) were nonserious. Not included were 57 (1.3%) reactions where seriousness was not assigned. MedDRA System Organ Classes (SOC): Card, cardiac disorders; Eye, eye disorders; Gastr, Gastrointestinal disorders; Genrl, General disorders and administrative site conditions; Immun, immune system disorders; Inv, investigations; Musc, musculoskeletal and connective tissue disorders; Nerv, nervous system disorders; Psych, psychiatric disorders; Renal, renal and urinary disorders; Resp, respiratory, thoracic and mediastinal disorders; Skin, skin and subcutaneous tissue disorders; Vasc, vascular disorders
14
Based on GE Healthcare Pharmacovigilance (PV) database, the post-marketing profile of Omniscan is characterized mainly by hypersensitivity reactions (31% of all reports received; Table 6), followed by gastrointestinal reactions (24%; nausea, vomiting and taste alteration; Table 4), skin reactions (about 16%; mainly NSF; Table 5) and reactions from the nervous system (11%;Table 8). All reports of NSF are coded as skin reactions. Twenty-five percent of all reactions were serious (Table 2); about half of which were NSF. Currently NSF cases constitute about 14% of all Omniscan reactions reported to GE Healthcare (Table 5).
Table 2 Adverse drug reactions and serious adverse drug reactions following administration of Omniscan
System Organ Class Cardiac disorders Eye disorders Gastrointestinal disorders General disorders and administration site conditions Immune system disorders Investigations Musculoskeletal and connective tissue disorders Nervous system disorders Psychiatric disorders Renal and urinary disorders Respiratory, thoracic and mediastinal disorders Skin and subcutaneous tissue disorders Vascular disorders Other (see Table 3) Subtotal Seriousness not assigned Total Adverse Reactions Count (%) 51 48 1047 273 1358 82 43 501 51 51 84 693 75 77 57 4491 (1.15) (1.08) (23.61) (6.16) (30.63) (1.85) (0.97) (11.30) (1.15) (1.15) (1.89) (15.63) (1.69) (1.74) (1.29) N/A Serious Adverse Reactions Count (%) 31 6 21 33 191 21 8 76 12 38 16 618 21 34 1126 (0.70) (0.14) (0.47) (0.74) (4.31) (0.47) (0.18) (1.71) (0.27) (0.86) (0.36) (1.94) (0.47) (0.77) (25.39)
4434 (100.00)
15
Table 3 Adverse drug reactions and serious adverse drug reactions following administration of Omniscan (Category Other in Table 2)
System Organ Class Blood and lymphatic system disorders Congenital, familial and genetic disorders Ear and labyrinth disorders Hepatobiliary disorders Infections and infestations Injury, poisoning and procedural complications Metabolism and nutrition disorders Neoplasms benign, malgnant and unspecified (incl cysts and polyps) Reproductive system and breast disorders Sum Other Adverse Reactions Count (%) 6 1 9 6 16 27 7 2 3 77 (0.14) (0.02) (0.20) (0.14) (0.36) (0.61) (0.15) (0.05) (0.07) (1.74) Serious Adverse Reactions Count (%) 3 1 3 5 12 7 2 1 0 34 (0.07) (0.02) (0.07) (0.11) (0.27) (0.15) (0.05) (0.02) (0.00) (0.77)
Table 4 Adverse drug reactions and serious adverse drug reactions of the gastrointestinal tract following administration of Omniscan
System Organ Class Adverse reaction term Gastrointestinal disorders Nausea and vomiting Taste alteration Adverse Reactions Count (%) 1047 986 (23.61) (22.24) Serious Adverse Reactions Count (%) 21 10 (0.47) (0.23)
See Nervous system disorders (Table 8)
Percentages of individual adverse reactions are related to the total count of the respective system organ class.
Table 5 Adverse drug reactions and serious adverse drug reactions of skin and subcutaneous tissue following administration of Omniscan
System Organ Class Adverse reaction term Skin and subcutaneous tissue disorders Nephrogenic systemic fibrosis Adverse Reactions Count (%) 693 608 (15.63) (13.71) Serious Adverse Reactions Count (%) 618 608 (13.94) (13.71)
16
4.4.1
Immune system reactions
Most (over 85%) of immune system reactions reported are non-serious, (e.g., rashes and urticarial reactions). Some severe and life-threatening anaphylactic reactions or shock have been reported (Table 6). To date, GE Healthcare has received one report of fatal hypersensitivity reaction since launch of the product.
Table 6 Adverse drug reactions and serious adverse drug reactions following administration of Omniscan
System Organ Class Adverse reaction term Immune system disorders Hypersensitivity Anaphylactic or anaphylactoid reaction Anaphylactic / anaphylactoid shock Adverse Reactions Count (%) 1358 1098 229 41 (30.63) (80.86) (16.86) (3.02) Serious Adverse Reactions Count (%) 191 32 118 41 (4.31) (2.36) (8.69) (3.02)
4.4.2
Renal reactions
There have been 35 occurrences of renal failure and impairment and one case of renal tubular necrosis (Table 7). The case reports concerning renal reactions occurred in patients with significant co-morbidity (including existing renal insufficiency in 30% of cases, diabetes mellitus in 14% of cases and multiple myeloma, hypertension/renal artery stenosis) and important risk factors including off-label use of Omniscan and concomitant administration of nephrotoxic drugs. Very little is known about the mechanisms of gadolinium nephrotoxicity.
Table 7 Adverse drug reactions and serious adverse drug reactions of the renal and urinary system following administration of Omniscan
System Organ Class Adverse reaction term Investigations Renal function analyses Renal and urinary disorders Renal failure and impairment Renal tubular necrosis Adverse Reactions Count (%) 82 9 51 35 1 (1.85) (10.98) (1.15) (68.62) (1.96) Serious Adverse Reactions Count (%) 21 5 38 34 1 (0.47) (0.11) (0.86) (66.67) (1.96)
17
4.4.3
Nervous system reactions
Reactions associated with the nervous system account for 11% of all spontaneous reports (Table 8). About 30 serious case reports concern convulsions or epilepsy or grand mal convulsion. Often a history of seizures or brain tumors was present. Convulsion and other reactions have occurred following off-label use of Omniscan (e.g., intrathecal administration). Few reports concerning other serious unlisted reactions like amnesia, coma, and memory impairment were received. Convulsions and other neurologic reactions may occur in patients with predisposing co-morbidity and/or following unapproved use of Omniscan.
Table 8 Adverse drug reactions and serious adverse drug reactions of the nervous system following administration of Omniscan
System Organ Class Adverse reaction term Nervous system disorders Ageusia, dysgeusia, hypogeusia Amnesia Coma Memory impairment Seizures (incl subtypes) Adverse Reactions Count (%) 501 70 5 5 1 44 (11.30) (13.97) (1.00) (1,00) (0.20) (8.78) 30 (5.99) Serious Adverse Reactions Count (%) 76 2 2 5 (1.71) (0.40) (0.40) (1.00)
4.4.4
Fatalities
Other than those related to NSF (Table 12), 13 fatalities have been reported. Acute renal failure, renal impairment or toxic nephropathy led to death in 5 patients, myocardial infarction was cause of death in 3 patients, pulmonary edema or respiratory arrest was fatal in 2 patients, one patient died of nosocomial infection, 1 due to a fall and another patient of anaphylactoid shock.
18
5 5.1
NEPHROGENIC SYSTEMIC FIBROSIS Description of NSF
NSF is a rare, acquired systemic disease. It is characterized by areas of thick, hardened skin commonly associated with brawny hyperpigmentation and preferentially localized to the extremities Figure 3 (Cowper 2000 and 2008, Mendoza 2006). Figure 3 The characteristic appearance of NSF
NSF was first described in the US in 2000, in a report identifying a case from 1997. It was initially thought to be confined to the skin and was initially named Nephrogenic Fibrosing Dermopathy (NFD), (Cowper 2000). In some patients, however, there is clinical involvement of other tissues (lung, skeletal muscle, heart diaphragm, esophagus, etc.) and the condition was re-named Nephrogenic Systemic Fibrosis (Cowper 2006, Ting 2003) to reflect its systemic nature. It can be a painful and debilitating condition that can contribute to a fatal outcome. NSF has been reported predominantly in patients with acute kidney injury, in patients with severely impaired renal function with a GFR about or below 30 mL/min/1.73 m2, or in patients
19
on hemodialysis, particularly in those with liver disease. The specific origin of the kidney disease does not appear to be related to the incidence of NSF (Issa 2008). At present, there is no evidence that patients without renal impairment, or those with mild renal impairment, are at risk of developing this disease (Thomsen 2006). In the spring of 2009, GE Healthcare received one case report of NSF with borderline moderate-severe renal impairment (estimated GFR 33 mL/min/1.73 m2 at time of contrast administration) see [see Section 5.4] for more details. 5.1.1 Additional Risk factors
Other factors suggested to be possible risk factors of NSF include: Edema (Cheng 2007) Metabolic acidosis (Cowper 2007b, Grobner 2006) Hypercoagulability states (Swaminathan 2006 and 2007b) Thrombotic events (Swaminathan 2006 and 2007b) High dose erythropoietin (EPO) (Swaminathan 2006, 2007a and b) Systemic inflammation (Sadowski 2007) Recent vascular surgery (Cowper 2007b) Recent transplant failure (Cowper 2007b) Sudden onset kidney disease with severe swelling of the extremities (Cowper 2007b) Liver affliction (severe liver failure, hepatorenal disease, liver transplant, cirrhosis) (Herlenius 2008, Shenoy 2008). Case studies indicate that many NSF patients have undergone a vascular surgical procedure or have experienced a thrombotic episode within approximately two weeks before disease onset (DeHoratius 2006). High GBCA exposure resulting from high and/or frequent dosing has been proposed as an important contributory factor to NSF risk (Collidge 2007, Prince 2008). There appears to be no predilection for any race or ethnic group. Neither does gender or age appear to be a risk factor. While NSF has been reported in children as young as eight years old and in the elderly, the majority of reports are in middle-aged patients (Cowper 2007a and b, Jain 2004). There is no evidence that immature kidney function itself (e.g., in neonates and infants) constitutes an increased risk of developing NSF. Reduced renal function in infants and neonates is physiological and normal for age, whereas the reduced renal function in adults in the setting of renal insufficiency is pathological. There is no known cure for NSF and treatment is generally supportive. Disease severity and progression varies among those affected. Dialysis has not been shown to improve symptoms although some experts believe that dialysis within 48 hours of GBCA use may reduce the risk
20
of the disease development. Symptoms tend to improve with improvement of renal function or following renal transplant, suggesting that the presence of an intact kidney may play an ameliorative role (Wollanka 2009).
5.2
General
Although the first known case of NSF was described in 2000 (Cowper 2000), a correlation between NSF and GBCAs was not suspected until a cluster of cases was reported in 2006 (Grobner 2006a and b). Since then several hundred papers have been published, ranging from case reports (both single cases and clusters), possible treatments, pathophysiological hypotheses, reviews, editorials and meta-analyses. The following review highlights key features through representative and up-to-date scientific publications. NSF is incompletely understood. Some of the more frequently cited hypotheses used to suggest the need for differential labeling (e.g., differential chelate stability and ensuing transmetallation with release of free gadolinium (Gd)) have significant weaknesses and do not explain why only 3-5% of the at-risk population develops NSF. Many NSF cases have been described in literature citing only one or a few cases each. Typically these papers lack homogeneity with regard to patient information. Information on renal function is lacking in the majority of cases and/or nonspecific terms like renal impairment or chronic kidney disease are used. Data on GBCA dose (single or cumulative) are seldom available nor is information on potential co-factors like inflammation, thrombotic events, nephrotoxic medications, duration of dialysis, and non-renal laboratory values. Therefore, this section includes only publications on larger series (clusters) of NSF cases. 5.2.1 Epidemiology
Epidemiological data show a high degree of variability. The overall incidence is extremely low, less than 0.00015% in 48 million Omniscan doses. Prince reported incidences of zero (0) in at-risk patients dosed with 0.1 mmol/kg and 0.17% with the 0.3 mmol/kg dose; incidence was 19% in acute renal failure (ARF) patients who did not receive hemodialysis within 2 hours after GBCA injection [Prince 2008 see Appendix A]. Others have reported incidences ranging from 0.06% and 0.43% [Chrysochou 2009, Deo 2007 and Wertman 2008 see Appendix A]. Similarly, prevalence ranged from zero (0) [Janus 2009 see Appendix A] to 18% [Rydahl 2008 see Appendix A] in patients with CKD stage 5, with other authors reporting prevalence ranging from 1.6 to 4.5% [Chen 2008, Heinz-Peer 2009, Lauenstein 2007, Rydahl 2008 see Appendix A]. Odds ratios (OR) reported in four studies ranged from 6.11-7.99 [Chen 2007, Othersen 2007 see Appendix A] to 22.3 [Broome 2007 see Appendix A] and 32.5 [Marckmann 2006 see Appendix A].
21
Collidge [Collidge 2007 see Appendix A] reported mortality in NSF patients to be the same as in non-affected patients who had received GBCAs. 5.2.2 Incidence, prevalence, mortality and demographic profile of the population at risk of NSF
Table 9 summarizes population risk demographic profile of patients with NSF. Table 10 presents information from published epidemiologic studies on NSF following administration of GBCAs focusing on incidence, prevalence, odds ratio, and mortality. Abstracts of publications cited in Tables 9 and 10 are provided in Appendix A Abstracts. Table 9 Demographic profile of the population at risk of NSF Population at risk of NSF Patients with ARF or severe chronic RI undergoing GBCA enhanced MR examinations. Risk factors and conditions that must be met to permit the development of NSF in patients with renal disease still need to be identified [Cowper 2007a see Appendix A], as only a subset of patients at risk actually develop NSF (cf. Table 5, in particular Incidence of NSF, Prevalence of NSF). A combination of factors, including altered kidney function, inflammatory burden, and exposure to gadolinium-based contrast agents may all play a role in development of NSF [Sadowski 2007 see Appendix A]. Three cases of NSF with no documented GBCA exposure have been published: [Wahba 2007 see Appendix A], 2 cases, [Collidge 2007 see Appendix A], one case. Probably not exposed to GBCA were another 11 patients with NSF: [Deng 2008 see Appendix A], one case, [Salman 2007 see Appendix A], 5 cases and [Morris 2007 see Appendix A], 5 cases. Demographic profile of target population NSF can affect persons of any age, including children and the elderly, but most cases involve middle-aged individuals [Cowper 2007a see Appendix A]. As seen in Table 12 (gender distribution) there is no gender difference.
22
Table 10 Data from published epidemiologic studies on NSF Incidence of NSF [Deo et al 2007 see Appendix A] A population of patients with ESRD in and around Bridgeport, was studied during an 18-month period. The incidence of NSF was 4.3 cases per 1000 patient-years. Each radiologic study using gadolinium presented a 2.4% risk for NSF. The association between gadolinium exposure and NSF was highly significant (P < 0.001). Fifteen patients developed NSF after gadolinium-enhanced MR imaging. All of them had an eGFR lower than 30 mL/min/1.73 m2, and 11 had acute renal failure or acute deterioration of chronic renal failure. The incidence of NSF after gadolinium-enhanced MR imaging without screening for renal function was zero among 74124 patients given standard dose of GBCA and 15 (0.17%) of 8997 patients given high doses (P < 0.001). The NSF incidence associated with a high dose of GBCA increased to 0.4% in patients in a chronic hemodialysis program and to 8.8% in those who had an eGFR lower than 15 mL/min/1.73 m2 but were not undergoing hemodialysis (P < 0.001). The NSF incidence in the patients with acute renal failure who received a high dose when their creatinine level was increasing was 19% (11 of 58 patients) when hemodialysis was delayed for longer than 2 days. [Chrysochou et al 2009 see Appendix A] [Wertman et al 2008 see Appendix A] No cases of NSF were observed in 562 (45% CKD stage 4 or 5) patients investigated at this one center. By extrapolation, 1/1735 patients screened for the ASTRAL trial developed NSF, giving a crude incidence rate of 0.06%. The incidence of NSF was one in 2913 patients who underwent gadodiamide-enhanced MR examinations and one in 44,224 patients who underwent gadopentetate dimeglumine-enhanced MR examinations.
[Prince et al 2008 see Appendix A]
23
Prevalence of NSF [Bridges et al 2009 see Appendix A] This study cohort was limited to patients who had received a dose of at least 40 mL of gadodiamide during a single imaging session, who underwent at least 1 year of clinical follow-up, and who had moderate to end-stage renal disease established within the previous 48 hours. NSF eventually developed in one of the 61 patients, yielding a prevalence of 1.6%. A total of 6 NSF cases out of 367 dialysis patients with ESRD who underwent MRI examinations with intravenous administration of GBCA were identified; all 6 patients were exposed to gadodiamide, 4 were exposed to at least one other GBCA. The prevalence of NSF was 1.63% in patients being exposed to GBCA (95% CI, 0.7-3.52%) and 0% in patients without exposure to GBCA (95% CI, 0-2.56%) which was statistically not significant (p=0.132). However, there was a statistically significant difference by using binominal tests and the general assumption of a 5% NSF prevalence among patients with ESRD being exposed to GBCA (p=.003). By using a general NSF prevalence rate of 2.5% no significant differences were found (p=.328) between ESRD patients being exposed to GBCA and those who did not receive these agents (odds ratio=.577). Prevalence of NSF among patients with chronic kidney disease (stage 5) was 18% (95% CI: 11%-27%). No cases were seen among 88 gadodiamide-exposed patients who had milder degrees of renal insufficiency. Between October 2003 and February 2007 a total of nine NSF cases were identified. All patients had undergone contrastenhanced MRI prior to the diagnosis of NSF. Only one gadolinium chelate had been used at this MRI center (Omniscan, gadodiamide; GE Healthcare). Of nine patients, eight were receiving dialysis at the time of the MRI scan. During the same time 312 dialysis patients received gadodiamide. Thus, the prevalence of NSF within dialysis patients exposed to gadodiamide was 2.6%. NFD/NSF was diagnosed in none of the 105 patients on hemodialysis but in one of the 22 patients on peritoneal dialysis.
[Heinz-Peer et al 2009 see Appendix A]
[Rydahl et al 2008 see Appendix A] [Lauenstein et al 2007 see Appendix A]
[Chen et al 2008 see Appendix A]
24
[Janus et al 2009 see Appendix A]
The 308 eligible patients in this trial had a mean age of 59.9 years, 59% were men, and 54% had stage 5 RI. 75% of those 308 patients received a gadolinium chelate. Among those patients who received a gadolinium chelate, 76% received gadoterate, 20% gadopentetate, 3% gadodiamide [7 patients] and 1% gadobenate. No cutaneous disorders, including NSF, were recorded after MRI.
Odds ratio [Marckmann et al 2006 see Appendix A] [Broome et al 2007 see Appendix A] [Cheng et al 2007 see Appendix A] Odds ratio for acquiring the disease when exposed to gadodiamide was 32.5 (95% CI 1.9 to 549.2, p < 0.0001). Seven (54%) patients became severely disabled, and one died 21 months after exposure. The odds ratio for development of NSF after gadodiamide exposure was 22.3. No other common event or exposure could be found. A matched case-control study was conducted in a St. Louis during January 2000August 2006. A confirmed case was defined as clinical findings (i.e., skin thickening or hardening) or skin biopsy findings consistent with NSF in a person with renal disease. Twenty-eight cases were identified, including 25 confirmed and three suspected cases. Nineteen of the 28 patients were included in the matched case-control study. Of the 19 patients 15 had received Omniscan, 3 Magnevist while one was a confounded case. Odds ratio for developing NSF after GBCA exposure was 6.11 (95% CI 1.9219.52) if GBCA exposure had taken place within the preceding 6 months, and 7.99 (95% CI 2.2228.77) if exposure had been during the preceding year.
25
[Othersen et al 2007 see Appendix A]
In 849 patients undergoing chronic dialysis from 2001 through 2006 time period, four of the 261 who had received gadolinium (1.5%) and none of the 588 not exposed to gadolinium developed clinically apparent disease. The odds ratio for developing nephrogenic systemic fibrosis was 6.671 [95% confidence interval (CI) 1.537-53.97] in patients with a single gadolinium exposure compared to patients without gadolinium exposure. This ratio increased to 44.5 (95% CI 2.362-2913) in patients with multiple gadolinium exposures compared to patients not receiving gadolinium. None of the 592 patients estimated to be in stage 3 or 4 of chronic kidney disease developed nephrogenic systemic fibrosis after exposure to gadolinium.
Mortality of NSF [Collidge 2007 see Appendix A] Fourteen of 1826 patients had a diagnosis of nephrogenic systemic fibrosis. Mortality was similar for affected and nonaffected patients. Patients with nephrogenic systemic fibrosis received a higher median cumulative dose of gadodiamide (0.39 vs. 0.23 mmol per kilogram of body weight, P = 0.008) and underwent more gadolinium-enhanced MR imaging than their nonaffected gadolinium-exposed counterparts.
CKD, chronic kidney disease; ESRD, end stage renal disease; GFR, glomerular filtration rate; MR, magnetic resonance; MRI, MR imaging; NFD, nephrogenic fibrosing dermopathy
In addition to the papers in Table 10, Agarwal (Agarwal 2009) performed a meta-analysis on NSF cases published in the literature. Seven of the 144 identified studies met inclusion criteria and were included in the analysis. The total number of patients in these seven studies was 4346. Possibly because it was the first reported as associated with NSF, gadodiamide was the sole or predominant GBCA in 4 of the studies, representing at least 3505 patients dosed. One study exclusively examined gadopentetate (Todd 2007). Except for the study by Todd the 6 other studies included by Agarwal are listed in Table 9 (above). (Broome 2007, Cheng 2007, Collidge 2007, Deo 2007, Marckmann 2006, Othersen 2007 and Todd 2007) Meta-analysis of the controlled trials demonstrated a significant association between GBCA exposure and NSF (OR 26.7; 95% CI 10.369.4) suggesting that this association was causal. The overall conclusion of a causal relationship between GBCA & NSF, is partially based on a misinterpretation of data from one of the studies (Otherson 2007), who clearly showed that a 'rechallenge' of patients did not result in the same outcome (e.g., recurrence of NSF). From a
26
methodological perspective, this evidence in the arena of causality assessment is quite substantive. While Agarwal writes that When a patient who had clinical resolution of NSF was re-exposed to gadodiamide, NSF reappeared again, the original paper (Othersen 2007) states that After 8 months of (hemodialysis) HD treatment, she recovered enough renal function (serum creatinine concentration 3.64.1 mg/dl) that chronic dialysis could be discontinued. After 6 weeks without dialysis her skin lesions began to abate and after 8 weeks without dialysis skin appeared completely normal. Six months after clinical remission of NSF, the patient underwent a second brain MRI with gadodiamide (7.5 mmol) exposure, but skin lesions did not recur. She remained free of the need for HD for more than 30 months with serum creatinine concentrations ranging between 2.3 and 2.8 mg/dl.
5.3
Global Postmarketing Reports of NSF Associated with Omniscan
GE Healthcare received the first notification of NSF case reports possibly associated with use of Omniscan in April 2006. Prior to this time there were four case reports in the GE Healthcare database that had been classified under different AE terminology; these were reclassified as NSF after the syndrome was recognized and a possible association with GBCA suspected. Based on data available to GE Healthcare (Table 11), it is apparent that more NSF cases have been reported in association with the use of Omniscan or Magnevist than with the other GBCAs. The number of cases for GBCAs other then Omniscan is incomplete as a full listing of all cases is not available to GE Healthcare. Table 11 GBCAs
Agent Omniscan Magnevist Gadovist ProHance
Number of Reported NSF Cases Deemed Related to Various

Apr-2006 25 N/A N/A N/A Feb-2007 119 21 N/A N/A Apr-2008 373 163 1 9 Jan-2009 532 411 2 9 Total 624 508 2 9 Data Source All reporting sources as of 30Jun-2009 (Bayer 29-Oct-2009) (Bayer 31-Jan-2009) (1 unconfounded Nov-2007 data Pennfield [Reilly 2008 see Appendix A] (2 unconfounded Nov-2007 data Pennfield [Reilly 2008 see Appendix A] (Guerbet website Mar- 2009) Published data from manufacturer not available. Cases taken from published literature [* Cheng 2007, Kallen 2008, ** Kadiyala 2009 see Appendix A].
MultiHan ce Dotarem Optimark
N/A
N/A
10
10
10
N/A N/A
N/A 3*
8 N/A
8 2**
10 5
N/A Published data not available

27
Potential causes for the difference in the numbers of reported cases with individual GBCAs should be considered. Being one of the earliest GBCAs approved, with a market share second only to Magnevist and physician perception of better renal tolerability, it is probable that Omniscan was used more extensively in patients with renal failure. Because Omniscan has a higher approved dose compared to other agents, individual and cumulative Omniscan doses may have been higher and/or the agent more frequently administered. Such use, compared to other GBCAs, is recognized in the American College of Radiology (ACR) usage of contrast guideline published in 2008. Figure 4 shows the number of NSF reports associated with Omniscan and the amount of the last dose received.
28
Figure 4 NSF reports associated with Omniscan. Size of last contrast dose
40 35
37
400 350 Number of NSF reports 300 250 200 150 100 50 0
43 4 163
368
30 Number of NSF reports 25 20 15 10 5 0 <0.1 >=0.1, <0.3 >=0.3 Last dose (mmol/kg body weight)
7 2
< 20
>=20, <=60
>60
Last dose (mL)
Not reported
Last contrast dose: Prior dose information for each case may or may not be available. It is unknown whether patients received one or many doses before NSF onset. This figure reports only the volume of the last known dose as identified by the reporter. Figure 1 also shows that, where Omniscan dose is known, the majority of NSF cases have been at or close to the upper approved dose limit of 0.3 mmol/kg, and very few above this.
GE Healthcare has been inclusive in the criteria it uses for reporting possible NSF cases. To prevent under-reporting to agencies, GE Healthcare Global Pharmacovigilance has coded to NSF all case reports with symptoms and signs suggestive of NSF, in addition to all cases with a reported diagnosis of nephrogenic systemic fibrosis or nephrogenic fibrosing dermopathy. Forty-three percent (43%) of all reported cases received by GE Healthcare have been received from non-Health Care Professionals (non-HCP), mostly from law firms. As these reporters routinely provide only minimal details it is likely that many among the 624 cases in the database are duplicates. Figure 5 shows cases broken down by the type of reporter - Health Care Professionals (HCPs) and Non-HCP (mainly law firms). The possibility that some of these are duplicate reports of cases previously reported by other sources cannot be assessed from the information available in these reports. GE Healthcare is unaware of the reporting criteria for other manufacturers and it is unclear if the numbers in Table 11 for these GBCAs include any cases from non-HCP (law firms) sources.
29
Figure 5 Omniscan-related NSF in 351 cases reported by HCPs and in 273 cases reported by non-HCPs by country (as of data lock point June 30, 2009)
300 250 200 150 100
57 268
HCPs Non-HCPs
167
50 0
De nm
28 1
20 3
17
25 10 9 7 7 4 1
The relatively high number of reports of NSF received during 2006 ands 2007, after the association of NSF and GBCAs was recognized, may be partly due to reporting bias as a result of greater physician awareness of the association as Omniscan was the first GBCA identified in reports. GE Healthcare was the first GBCA manufacturer to inform healthcare professionals about the possible association between NSF and GBCAs, including Omniscan, and to actively solicit reports of cases. This may have led to hindsight bias, in which medical notes of patients who had received Omniscan were selectively reviewed following awareness of Dear Doctor letters or media coverage, resulting in reports of NSF. 5.3.1 Clustering of Cases
Figure 6 shows that as of June 30, 2009 the majority of reported cases associated with Omniscan have occurred in the USA.
Ge
30
O Co the un r 1 tr 1 ie s
US A
UK
pa n
Be l
Ca na da
Au st ria
Fr an ce
an y
ar k
um
rm
Ja
Sp ai
gi
Figure 6 Omniscan-related NSF (624 cases) by country (data lock point June 30, 2009)
500 450 400 350 300 250 200 150 100 50 0
U Ge K rm an y Au st ria Ja pa Be n lg iu m Fr an ce Sp ai n Ca na d No a rw Sw ay itz er la n Ta d iw a Au n st ra li a C Ne hil e th er la nd Si s ng ap or Sw e ed en Fi nl an d Gr ee ce Br az il US De A nm ar k
435
57 29 23 17 10 9 7 7 5 4 4 4 2 2 2 2 2 1 1 1
Of the 435 US Omniscan-associated NSF case reports where the imaging facility was identified (163 case reports; 37%) a total of 49 distinct facilities were identifiable. These 49 facilities represent approximately 2% of the approximately 2100 US imaging centers using Omniscan during recent years. Hence, approximately 98% of US centers using Omniscan have not reported any NSF cases. Further analysis of these 163 case reports revealed that 98 (60%) of them were received from just 9 US centers (0.4% of the total number of US imaging centers); each center reported 5 or more cases. Outside the US, the country with the greatest number of NSF case reports is Denmark, where 57 cases have been reported to the Danish Medicines Agency. Fifty (88%) of these cases were reported by two centers, Herlev Hospital (33 cases) and Skejby Sygehus (17 cases). Globally, a small number of sites that have used Omniscan have reported cases of NSF. This concentration of cases at a small number of centers suggests that that the distribution of cases is non-homogeneous and non-random. This suggests inter-center differences in either the types of patients given Omniscan, and/or the way in which Omniscan is used. The relevance of clustering has not yet been explained, but serves as an example of the lack of understanding that exists about the occurrence of NSF in patients following use of GBCAs. One theory is that NSF has occurred more frequently in centers that perform a high number of MR angiography (MRA) a procedure that is considered off-label in the US and some other countries. Published literature indicates physicians often used higher-than-standard doses of GBCAs in patients with severe renal impairment, and that these patients constitute a large number of the patients referred for MRA.
31
5.3.2
Characteristics of Reported Omniscan-Associated NSF Cases
Table 12 provides an overview of and descriptive information about NSF cases with regard to age groups, gender, type of renal failure, stage of chronic renal insufficiency and concomitant diseases other than severe chronic renal impairment, which may be additional risk factors. Some concomitant medications used routinely in patients on hemodialysis, namely, erythropoietin (EPO) and high doses of i.v. iron supplements, have been investigated as possible co-factors in NSF development. These are the only concomitant medications mentioned and discussed to some extent in the literature (Swaminathan 2007, Pryor 2007). The number of confounded cases (i.e., those where other GBCAs have been administered in addition to Omniscan) is 119 out of 624 (19%). Table 12 Details of NSF cases associated with Omniscan
Nephrogenic systemic fibrosis Seriousness /outcomes Details of NSF cases In total, 624 reports concerning NSF are included in GE Healthcares global safety databases; 351 case reports were received from HCP sources, 273 from Non-HCP sources. An unknown number of duplicates is expected to be contained in the number of cases reported from Non-HCP sources. All reported are assessed to be serious. Death irrespective of cause No information that patient was not alive at reporting 123/624 (20%) 501/624 (80%)
Of the fatal cases, NSF reported to contributed to death Cause of death reported to be unknown Other causes of death Cause not reported 85/123 (69%) 5/123 (4%) 20/123 (16%) 13/123 (11%) 399/624 (64%) 85/624 (14%) 21/624 (3%) 3/624 (0%) 116/624 (19%)
Not resolved Death Resolving Resolved Not reported
32
Nephrogenic systemic fibrosis Severity and nature of risk
Details of NSF cases NSF reported to have caused disability NSF did not cause disability or caused minor symptoms Disability not reported or unknown 271/624 (43%) 57/624 (9%) 296/624 (47%)
Age distribution
Age or age group details are available in 340 of 624 (55%) of the NSF case reports. Newborn or infant Child (1 to 12 years of age, the youngest was 9) Adolescent (12 to 18 years) Adult (18 to 65 years) Elderly (65 years or older) Age/age group not reported or unknown 0/624 (0%) 2/624 (0%) 4/624 (1%) 262/624 (42%) 75/624 (12%) 281/624 (45%) 321/624 (51%) 285/624 (46%) 18/624 (3%) Non-HCP source 0/273 (0%) 1/273 (0%) 13/273 (5%) 0/273 (0%) 259/273 (95%) Total 1/624 (0%) 31/624 (5%) 231/624 (37%) 26/624 (4%) 335/624 (54%)
Gender distribution
Gender is available in 606 of 624 (97%) of the NSF case reports. Male Female Gender not reported or unknown
Renal function and type of renal failure (chronic vs. acute)
Renal function assessment is available in 289 of 624 (%) of the NSF case reports Renal function Moderate CKD (stage III) Severe CKD (stage IV) End stage CKD (stage V) Acute renal failure (ARF) Renal function parameter not reported/unknown HCP source 1/351 (0%) 30/351 (9%) 218/351 (62%) 26/351 (7%) 76/351 (22%)
Concomitant liver disease
Information regarding concomitant liver disease provided in 105 of 624 (17%) of the NSF case reports. All reports are from HCP sources except one. Liver disease No liver disease Not reported or unknown 27/624 (4%) 78/624 (13%) 519/624 (83%)
33
Nephrogenic systemic fibrosis Concomitant medication Erythropoietin
Details of NSF cases
Information regarding erythropoietin was provided in 85 of 624 patients (14%). All reports are from HCP sources except one. Erythropoietin No erythropoietin Not reported or unknown Iron substitution Information regarding iron substitution was provided in 30 of 624 patients (5%). All reports are from HCP sources. Iron substitution No iron substitution Not reported or unknown 15/624 (2%) 15/624 (2%) 594/624 (95%) 60/624 (10%) 25/624 (4%) 539/624 (86%)
As of data lock point 30-Jun-2009; HCP = healthcare professional
5.4
Type of renal failure and stage of chronic renal failure
Cowper regards renal insufficiency as the only immutable epidemiologic feature of NSF (Cowper 2007b). The renal disease may be acute, chronic, or transient; most patients have chronic renal insufficiency and are usually dialysis-dependent. In all cases evaluated so far, the renal disease predates or arises concurrently with the skin lesions of NSF. The cause, duration and the severity of the underlying renal disease do not appear to be directly related to the severity of the NSF (Cowper 2007b). Of the 351 patients in NSF case reports from an HCP source, 218 (62%) had end stage chronic renal insufficiency. Thirty (9%) of these patients had severe chronic renal insufficiency, i.e., a GFR below 30 mL/min/1.73 m2 (Figure 7). Acute renal failure was reported in 26 (7%) of cases.
34
Figure 7 NSF Reports Associated with Omniscan by Stage of Kidney Disease Stage (HCP and non-HCP Sources)
400 Number of NSF reports 350 300 250 200 150 100 50 0
1 26 31 231 335
Moderate Acute RF
Severe
End stage
Not reported
The 26 acute renal failure cases were analyzed for six different factors considered to be important co-factors for development of NSF (Cowper 2007b, Swaminathan 2007a). Thirteen (50%) had liver disease, including hepato-renal syndrome, transplantation, and cirrhosis; 6 (23%) were on hemodialysis; 3 (11.5%) had infections; 12 (46%) were status post surgery; 4 (15%) had experienced thrombotic events; and 9 (34%) had a history of transplantation. The median number of factors present in these patients was 3, indicating that in addition to acute renal failure, they had multiple concurrent conditions that also have been associated with the development of NSF. Until the spring of 2009 GE Healthcare had not received any reports of NSF in patients with moderate chronic renal failure (GFR 30 - 60 mL/min/1.73 m2); however, GE Healthcare has since received one such case associated Omniscan dosed in 2007. It is not certain, however, if this patient was truly in moderate renal failure at the time of exposure (see detailed description that follows). The patient is a female in her mid-fifties in chronic renal failure due to multiple chronic health conditions, including diabetes. During the summer of 2007, she went to the emergency room with a severe headache. The first day at the hospital she underwent MRI/MRA of the head and neck with and without contrast due to a presumptive diagnosis of a cerebral vascular accident. The next day she underwent a renal MRI with contrast due to a presumptive diagnosis of renal artery stenosis.
35
Both contrast procedures were done with 30mL Omniscan, a cumulative dose of 60 mL within 24 hours. GFR at the time of first administration was 33 mL/min/1.73m2, at second administration, i.e. the next day, 40 mL/min/1.73m2, and remained between 30 and 31 mL/min/1.73m2 during admission. After an unknown interval subsequent to Omniscan administration, she experienced a tightening and burning in her hands and arms, tingling and drawing up of the skin of her right side, and progressive skin tightening and contractures of her feet. In the fall of 2007, approximately four months after receiving the two contrast procedures, she had a dermatological consultation with a skin biopsy, and NSF was diagnosed. The patient progressed to Stage IV chronic renal failure, and continued to experience NSF symptoms. To date, this is the only case of NSF reported in Stage III chronic renal failure. However, the patient was suffering from multiple acute pathologies currently accepted as increasing the risk for NSF. Using the extended MDRD calculation (Modification of Diet in Renal Disease) of GFR, adjusted for weight and serum BUN (Blood Urea Nitrogen), the GFR when she was hospitalized in summer 2007 (second MRI) was 27.5 mL/min/1.73m2, i.e., the patient was in Stage IV chronic renal failure. Two weeks after hospital discharge, her records indicated that she was in Stage IV chronic renal failure. A company-performed GFR calculation at that time (extended MDRD equation) was 21 mL/min/1.73m2. The initially reported GFR of 40 mL/min/1.73m2 when she was hospitalized in summer 2007 may have been artificially elevated due to intravenous hydration.
5.5
Trending
In April 2006 GE Healthcare received the first notification of NSF case reports possibly associated with use of Omniscan administered (on average) four years prior to reporting. If reports of NSF associated with Omniscan are classified by date of onset (as opposed to date of report) it can be clearly seen that the great majority of cases occurred prior to the index cases in 2006, and after 2006 there has been a dramatic decline in the number of new-onset cases (Figure 8). As of June 30, 2009, there have been no new non-confounded cases with known onset of NSF after September 2007 which were plausibly associated with Omniscan, a period of over 2 years.
36
Figure 8 Date of onset - NSF cases associated with Omniscan

100 90 80 70 60 50 40 30 20 10 0
<2002 2002 2003 2004 2005 2006 2007 Number of cases
88
87
47 27
48
23
19 0
2008
0
2009
As of data lock point 30-Jun-2009NB: year of onset of NSF may be different from year the diagnosis of NSF was established or reported. In 284 cases the year of onset of NSF is not known
Figure 9 reflects the percentage of NSF cases associated with Omniscan relative to the percentage of the total sales of the product per country. This analysis shows that NSF reporting varies greatly occurring more frequently in some countries (e.g., Denmark, the UK, and Austria) and less frequently in others (e.g., France and Germany). In 16 EU countries there have been no reports of NSF. There is no clear explanation for this mismatch, but it may be linked to how GBCAs are used within these countries, including the doses commonly administered and the types of patient receiving higher doses. The profile in figure 10 would not appear as it does if the risk of NSF were inherent in product-related factors only. If reporting frequency varies up to 50-fold for one GBCA, caution is necessary when comparing incidence among GBCAs, not all of which have been used (or are approved) in the same countries, at the same dose, over the same time period, or in the same patient populations.
37
Figure 9 Volume sold relative to NSF cases

67% 58%
20.00%
Analysis Based Upon US and EU Data Only Volume Data from 2002 - 2007
% of Total in Reported US and EU Countries
% of NSF Cases
15.00%
% of mLs sold
Cases not proportional to volume sold
10.00%
5.00%
0.00%
US A i um
in
an ce
l an d
-N oN SF
wa y
ds
en
d Fi n l an
ma n
Au str i
Sp a
Sw ed
Be lg
er l an
Sw i tz er
Ki ng
No r
Fr
EU
ed
Un it
38
Th
eN
e th
De n
Ge r
ma rk
do
ACTIONS TAKEN TO ENSURE PATIENT SAFETY
In April 2006 GE Healthcare became aware of reports of NSF associated with Omniscan and responded by submitting 15-day safety reports to the Omniscan NDA. In May 2006 the company began months of open, bi-directional, and ongoing communications with the Division of Medical Imaging and Hematology Drug Products to keep the Agency informed and to discuss appropriate means of communicating information about NSF to healthcare professionals. GE Healthcare diligently communicated with all regulatory authorities where the product was registered and informed healthcare professionals within and outside of the United States, including issuance of a Global Safety Alert to regulatory agencies worldwide on May 9, 2006. In June 2006, parallel GE Healthcare and FDA communications were issued to HCPs about reports of NSF in relation to use of GBCAs, including Omniscan, in patients with chronic, severely-impaired renal function. Additional reports of NSF were received in association with other GBCAs leading GE Healthcare and FDA to provide concurrent updates to HCPs in December 2006. This update strengthened cautionary advice regarding GBCA use and NSF risk in patients with moderate to severe renal dysfunction, usually associated with exposures at the high end of the dose range. In May 2007 FDA held a joint teleconference with and submitted letters to manufacturers of the GBCAs on the US market requesting class labeling changes to the package inserts, submission of letters to appropriate healthcare professionals about the requested labeling changes, and clinical trial proposals to assess the magnitude of risk for developing NSF in patients with moderate to severe renal insufficiency. Working together with the Medical Imaging and Contrast Agent Association and FDA, on September 12, 2007 the manufacturers mailed a joint letter to healthcare professionals informing them of class labeling revisions to add a boxed warning (see italicized text below) and updates to the warning sections of the package inserts of each of these products. Copies of the revised package inserts for each product were provided with the letter. A copy of this communication [see DDR Letter Appendix F] and the Omniscan Package Insert [see Omniscan Package Insert Appendix G] are provided.
39
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate < 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. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any re administration (See WARNINGS). For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to assist elimination, although the usefulness of hemodialysis in the prevention of NSF is unknown. In addition to the clinical trials requested by FDA, GE Healthcare initiated a program of nonclinical studies targeted at better understanding the association between GBCAs and NSF. Details of these Nonclinical and clinical studies are provided in Section 7.4 and in the Appendices. [see Appendices B, Nonclinical Studies] [see Appendices E, Table of Nonclinical Trials]
40
7 7.1
STUDIES OF NSF Investigations in Human Bone
Two clinical studies that were published prior to the suspicion of an association between NSF and GBCAs have suggested that higher levels of gadolinium in human bone following gadodiamide administration compared to gadoteridol were evidence of greater instability or in vivo dechelation of gadodiamide (Gibby 2004, White 2006). Deposition in bone was examined in patients with normal kidney function undergoing hip replacement after gadoliniumenhanced MRI (Gibby 2004). Even in normal patients small amounts of gadolinium were found to be retained in bone after administration of both gadodiamide (p=0.0004) and gadoteridol (p=0.0165). The higher concentration of gadolinium in the bone of patients who received gadodiamide was attributed to differences in stability of the chelate of gadoteridol compared to gadodiamide (Gibby 2004, White 2006); the relative levels of gadolinium do not correlate with stability constants of the two agents, however. Moreover, the analytical method used (Inductively Coupled Plasma Atomic Emission Spectroscopy (ICP-AES)) cannot distinguish between gadolinium chelate and unchelated free or precipitated gadolinium. This fact, along with differences in timing of sample collection (less for gadodiamide), raises questions of the validity of the comparison. If retained gadolinium were important to development of NSF one would expect cases of NSF in a broader spectrum of patients. Currently there is no evidence that NSF can develop in individuals with normal renal function so the meaning of retained gadolinium is uncertain. Except for the one patient with moderate renal impairment [see Section 7.4], NSF has been reported only in a small percentage of patients with severely impaired renal function (SIRF), end stage renal disease (ESRD) and those in acute renal failure (ARF). Reports of NSF cases not exposed to GBCAs raise questions about the effect of retained gadolinium (Wahba 2007).
7.2
Investigations of Human Skin
High reported deposition of gadolinium (mean of 70 ppm) in skin samples from four of seven patients with NSF (High 2007). A sample of uninvolved skin (with actinic keratosis) from a patient with NSF had a gadolinium concentration of 5 ppm. The Gd3+-species was detected in areas of fibrosis in NSF tissue and in NSF tissue co-localized in areas of dermal inflammation rich in macrophages. Gadolinium was detected (1 to 2270 cps/mm2) in cutaneous biopsies of NSF associated with P, Ca, and Na in tissue deposits (Thakral and Abraham 2007). Since Gd3+-species were considered to be intracellularly located, possibly within lysosomes, it was proposed that NSF was caused by precipitated gadolinium (Gd3+)-species being phagocytosed by macrophages which in turn released the cytokines and growth factors that stimulate fibrosis (High 2007). As these studies did not differentiate between chelated and free gadolinium, this theory may not be correct as an explanation of the presence of Gd3+-species in NSF tissue. The basis for a
41
role of gadolinium is that free Gd3+ can be toxic to cells; this is the reason gadolinium is chelated for use as an MR imaging agent. There is emerging evidence, however, to suggest that even chelated-Gd3+ might initiate pathological processes that were previously attributed to precipitated Gd3+ alone. To identify what gadolinium species may be important in the development of GBCA-associated NSF, several collaborative studies have been carried out. The results of these new studies suggest that gadolinium chelate also may trigger the development of NSF. A summary of these mechanistic studies is described in Section 7.4. [see Appendices B, Nonclinical Studies] [see Appendices E, Table of Nonclinical Trials].
7.3
Investigations of Human Serum
Frenzel et al have measured the complex stability and gadolinium apparent dissociation rate of GBCA in human serum at pH 7.4 and 37C over 15 days using a chelating Sepharose column connected to an ICP-MS (inductively coupled plasma mass spectrometer) (Frenzel 2008) and detected the release of gadolinium from GBCA incubated with serum taken from normal human volunteers in vitro over a period of 15 days. Release was ~15 to 20-fold higher for gadodiamide, gadobenate, and gadoversetamide, respectively, than for gadopentetate, gadoterate and gadoteridol. These observations, however, do not correlate with the relative numbers of NSF cases reported for the different GBCAs.
7.4
In Vitro Studies
It has been hypothesized that trans-metallation, a process in which Gadolinium (Gd3+) is displaced from the chelate complex, may drive Gd3+ accumulation in the tissues and trigger development of NSF. Direct exposure of human fibroblasts, monocytes and macrophages to concentrations of GBCA equivalent to those in blood after 2-3 fold the standard clinical dose of GBCA) stimulate profibrotic and pro-inflammatory responses (Bhagavathula 2009, Del Galdo 2008, Edward 2008, Varani 2009, Wermuth 2009a and b,). The rapid effects of GBCA on these cells strongly suggest that chelated gadolinium is a bioactive species which could be a potential factor in the development of NSF in susceptible patients. (Newton 2009).
7.5
GE Healthcare Nonclinical Studies
GE Healthcare has an ongoing program of Nonclinical bioanalytical studies, in vivo safety studies, and mechanistic studies on human cell responses and signaling to better understand the development of NSF. Key findings from mechanistic and animal studies are presented in the appendices. [see Appendices B, Nonclinical Studies] [see Appendices E, Table of Nonclinical Trials] The study results suggest that all forms of chelated gadolinium are potentially bioactive species under certain conditions. (Newton 2009) Thus it would be impossible to determine the gadolinium species involved, if any, in a patient diagnosed with NSF. In addition, not all tested donor cells (macrophages, monocytes and fibroblasts) responded in a concentrationdependent way to GBCAs, suggesting a genetic component to the development of NSF.
42
Based on the Nonclinical studies in published literature and conducted by GE Healthcare, an alternate hypothesis has been proposed as a mechanism for the development of NSF. [see Appendix D: Alternate Hypothesis]
7.6
Published Clinical Study
The largest published clinical study to date is a retrospective analysis of 83,121 patients at two large academic medical centers. Of the 74,124 patients who received Omniscan (0.1 mmol/kg) in this study none developed NSF. Of those receiving higher doses (0.2-0.4 mmol/kg), 15 of 8,997 developed NSF, an incident rate of 0.17% in patients who were not screened for renal function; in patients with an eGFR 15ml/min who were not undergoing hemodialysis incidence was 8.8%. Other significant cofactors identified were pro-inflammatory events, delayed hemodialysis, lower pH, lower eGFR, elevated phosphate, and younger age (Prince 2008).
7.7
GE Healthcare Post-Marketing Clinical Trials
As noted in Section 6, manufacturers of GBCAs were requested by FDA to perform postmarketing clinical trials to study the risk of NSF in at least 600 patients with moderate and 400 patients with severe renal insufficiency using their individual GBCA. After a series of design discussions with FDA the GE Healthcare protocol (GE-141-071) was approved on December 29, 2007 and submitted to Omniscan IND 32,218 on January 11, 2008. At the request of Western IRB (WIRB; Olympia WA) the protocol was amended to indicate that the study would be performed only at sites that routinely use Omniscan in the study population. Additional changes were made to: 1) Allow sites to recruit patients from only one of the two categories of kidney disease (e.g., if policies at the clinical site prohibited use of gadolinium contrast agents in subjects with a GFR below 30 mL/min/1.73 m2). 2) Recommend that the diagnosis of NSF be based on criteria developed recently by a working group sponsored by the American College of Radiology [unpublished work by Cowper 2008]. 3) Require determination of renal function (GFR) within 24 hours prior to dosing with Omniscan, for all subjects not on dialysis. Amendment A01 was accepted by WIRB on 16 August 2008 and the amendment submitted to the Omniscan IND on July 29, 2008. A list of potential study sites was compiled from internal databases of Omniscan users and internal files of previous trial sites for Omniscan or nephrology studies. Each site was contacted and asked if they currently used Omniscan in the renally impaired population, and, if so, if they would consider participation in the Registry study. Sites which did not respond after 3 attempted contacts were considered uninterested and not contacted further.
43
Of the 684 sites contacted, 680 (99%) declined participation in the study for the reasons summarized in Table 13. Of these sites, 417 (61%) were no longer using Omniscan (260 sites, 38%) or did not use it in the populations to be studied (159 sites, 23%). Reasons for declining to participate are summarized in Table 7.
Table 13 Reasons that Sites Declined Participation in Study GE-141-071 Following Initial Contact
Percent of Reason (1) (2) (3) (4) (5) (6) the site no longer uses Omniscan the site does not use Omniscan in the protocol patient population the site has not responded after 3 contacts by GE Healthcare personnel the site would not specify any reasons the site does not have a clinical research infrastructure to enable participation in the trial the site does not prescribe a specific contrast agent (e.g., they are a research nephrology office) or the site does not have MRI capabilities Sites 38% 23% 17% 9% 6% 6%
TOTAL
99%
In November 2008 GE Healthcare held a teleconference to discuss the clinical trial with FDA who agreed that GE Healthcare could separate the study into two separate protocols (one each to study patients with moderate or severe insufficiency). FDA also agreed that GE Healthcare could enroll non-US patients. A new protocol, GE-041-075, with patients with moderate renal insufficiency was prepared and submitted to the Omniscan IND in April 2009. It was amended (A01) based on comments from potential study sites and submitted to the Omniscan IND on October 21, 2009. GE Healthcare has contacted approximately 200 potential sites worldwide (US, Canada, Brazil, China, Taiwan, Korea, Singapore, Thailand, India, Spain, Italy, Sweden, Germany, and Norway) to participate in study GE-041-075. Table 14 summarizes the current status of the study.
44
Table 14 Omniscan Safety Study (GE-041-075) Summary October 2009

COUNTRY US/8 SITE STATUS 6 sites confirmed to participate 3 sites actively recruiting patients (Drs Weiland, Schoepf, and Brown) 4 patients enrolled, all by Dr Weiland Reviewing screen log showed non-qualified cases were either due to GBCA injection in past 12 months or eGFR>60 CANADA/2 2 sites confirmed to participate Dr Larose (Quebec City) is active and has enrolled one patient. Dr Dennie (Ottawa) has insurance issue BRAZIL/6 4 sites confirmed to participate 2 more possible. EC submission expected in October (insurance delay) CHINA/13 7 had IEC approval since August, waiting for contract 6 in the process submitting to IEC TAIWAN/4 4 sites confirmed to participate 3 IEC submission and wait for decision; 1 is to be submitted SPAIN/10 10 sites confirmed to participate 2 sites Central Ethics Committee approval Health authority submission done INDIA/4 4 sites confirmed to participate All local Ethics Committee submissions are complete and are pending final reviews DCGI submission of amendment 1 done 0 0 0 0 0 1 ENROLLMENT 6
A total of 47 sites have expressed interested in participating in the study and 44 have confirmed their participation. As of October 15, 2009, 15 sites have received IRB approval, of which four have been initiated and enrolled a total of 7 subjects. The remaining sites are finalizing contract issues or have requested an amendment prior to starting. GE Healthcare has made progress in acquiring study sites and has the infrastructure in place to move forward with subject enrolment to meet our FDA commitment.
45
ASSESSMENT OF DIFFERENTIAL RISK
There has been much discussion around the issue of differential risk among GBCAs with regard to NSF. Suggested differences have focused on agent stability, Nonclinical studies and findings, and clinical case reports. All of these data sources have limitations and require prudence and appropriate scientific considerations to assess these proposed differences. GE Healthcare has considered all of these sources and the relative evidentiary basis they provide. Based upon our in-depth analysis of the differential risks proposed, GE Healthcare provides its assessment as it relates to the question of differential risk among GBCAs.
8.1
GBCA Physical Chemistry
Although there is no direct evidence that inorganic Gd3+-species trigger NSF, the hypothesis that dechelated inorganic Gd3+ might cause NSF is based upon the observation that renal insufficiency leads to the reduced elimination of GBCA from the body (Joffe 1998, Staks 1994, Tombach 2000 and Townsend 2000). This fact has been coupled with known differences of in vitro chemical stability constants among members of the class of GBCAs, on the theory that they impact the rate and extent of Gd3+ release from GBCA in the body (Ide 2007). This release has been theorized to trigger inflammatory and fibrotic responses leading to NSF. None of the various measures of in vitro stability, however, has shown a clear or consistent relationship to physiologic effects in vivo or to clinical GBCA-associated NSF. Additionally, the differences in numbers and frequency of NSF case reports across the various GBCAs are orders of magnitude less than would be predicted based upon chemical stability considerations alone. While gadolinium is a known toxin, there is no compelling evidence demonstrating that free gadolinium causes NSF. It has been shown that direct exposure of human fibroblasts, monocytes and macrophages to medically relevant concentrations of intact GBCA stimulate profibrotic and proinflammatory responses which have been identified as risk factors for NSF. (Bhagavathula 2009, Edward 2008, Del Galdo 2008, Varani 2009 and Wermuth 2009a and b) This rapid effect of GBCA on these cells strongly suggests that chelated gadolinium may contribute to the development of NSF in susceptible patients. Therefore, theories that focus solely on physicochemical characteristics of GBCAs, such as chemical stability, as explanations for the development of NSF are incomplete and flawed.
8.2
Utilization Rates
Review of clinical case reports from the post-marketing safety database necessitates attention to differences in utilization of the GBCA, when considering differential risk. Determining relative risks of the various GBCAs based on differences in numbers of spontaneous reports requires clear understanding of the relative utilization of the different agent, not just absolute
46
distribution numbers. Comparative utilization is not well understood across the class of GBCAs but would include items discussed below. The disproportionate use of some GBCAs in high risk groups due to pre-2007 labeling restrictions (in patients with renal impairment) for other members of the class coupled with probable HCP perception of better safety may have led physicians to a higher degree of offlabel use with agents such as Omniscan than for other GBCAs, including use in patients with renal impairment. Many NSF cases are confounded by the use of more than one agent. Consequently it cannot clearly be said whether the occurrence of NSF is associated more with one GBCA than another. Similarly, differences in criteria and definitions used to determine whether an event is considered to be a reportable case of NSF will create inequality in reporting. Without a common definition of what constitutes a reportable case of NSF, it is difficult to make direct comparisons of risk based solely on the absolute number of cases reported. To prevent from under-reporting to regulatory agencies GE Healthcare has reported all NSF cases received regardless of the degree of diagnostic certainty of NSF. Differences regarding where and when individual GBCAs were approved and on the market impact the number of patients exposed to each GBCA, and thus the number of cases reported. If certain agents have more restricted labeling, then they may have been used less often in high risk populations biasing any comparison based solely on reported cases. The same may be said for differences in use patterns within and across geographies as evidenced by disparate reporting among global markets and clustering of reports among a small number of centers. Uncertainty about the number of individual cases of NSF that have been reported will incorrectly inflate the number of cases. It is probable that Omniscan case numbers include many duplicates due to reporting through several channels. Over half of the cases in the GE Healthcare pharmacovigilance database have been received from non-HCP sources, mostly from law firms. Most of these provide insufficient detail to determine whether or not they are duplicates.
8.3
Other Safety Considerations Among GBCAs
In assessing benefit-risk it is important to consider the overall safety profiles of members of the GBCA class. GBCAs are associated with other adverse experiences in addition to NSF. As is true with other contrast agents, hypersensitivity events are a matter of concern for GBCAs but are reported to varying degrees across the class. Table 15 provides a comparison of safety (other than NSF) for three of the GBCAs first on the US market: gadopentatate dimeglumine ((Magnevist), gadoteridol (ProHance) and gadodiamide (Omniscan). The comparison is from a published survey focusing on hypersensitivity reactions conducted by the American Society of Neuroradiology program directors (Murphy 1999). The data are compiled from responses by 53 of 105 imaging centers representing experience with an estimated 835,535 doses over an eight-year period prior to experience with NSF. No deaths were reported with any of the agents; however, there is a
47
clear difference between the agents in regard to the number of hypersensitivity reactions; the fewest were reported for gadodiamide (Omniscan). While there are limitations to data collected in this manner they provide a reminder that assessing the risk-benefit profile of an agent or class of agents like GBCAs necessitates a multifaceted approach. Table 15 Adverse Reactions Gadopentatate Dimeglumine Doses Administered Non-Allergenic Reactions Mild Allergenic Reactions Moderate Allergenic Reactions Severe Allergenic Reactions Total Adverse Reactions 687,255 314 (0.046) 107 (0.016) 28 (0.004) 5 (0.001) 454 (0.066) Gadoteridol 64,005 171 (0.267) 49 (0.077) 29 (0.046) 11 (0.017) 260 (0.406) Gadodiamide 74,275 11 (0.015) 12 (0.16) None None 23 (0.031)
48
CONCLUSIONS
Gadolinium based contrast agents (GBCA) are highly beneficial for enhancement of MR imaging and are well tolerated by over 99% of patients. Reports of the recently identified condition of nephrogenic systemic fibrosis (NSF) in association with the use of these agents have negatively impacted their risk-benefit profile. While an association has been established between the class of GBCAs and development of NSF, current available data do not establish a definitive causal relationship. What is clear is that the risk is greatest, if not entirely, within the sub-population of patient with renal insufficiency, typically severe and associated with endstage kidney disease. While the number of reports of NSF varies across the class and does not appear to be linked directly to distribution, there is no definitive evidence establishing that the risk of acquiring NSF is greater for one agent than for the others in the class. Differences in general safety profile, approved dosing, and utilization by healthcare providers (HCPs) make assessment of differential risk of NSF almost impossible. Accordingly, in the absence of clear evidence of risk differentiation among GBCAs it is prudent to apply warnings and precautions consistently across the class. Failure to do so may lead to other safety issues (e.g., hypersensitivity reactions) through a misperception of safety of some agents over others. Lack of consistency could put all patients, including those with severe renal insufficiency, at risk by inappropriately implying that certain agents can be used with increased frequency and less risk in patients with significant renal dysfunction. Inappropriate overall safety assessment could effectively dilute the relevance of the overall benefit-risk of these agents and may not serve the physician/patient community well, specifically those patients with renal insufficiency. We believe that such differentiation between GBCAs should only be based on reliable scientific evidence for effective use of these agents. Actions that imply certain agents can be used with increased frequency and pose less risk in patients with significant renal dysfunction must be based on substantive data. In response to the identification in 2006 of an association between use of GBCAs and the development of NSF, an extensive communication campaign was initiated by FDA and GE Healthcare to inform HCPs about the potential risk and was followed by class labeling mandated by FDA (and other global regulatory authorities). Since implementation of these label restrictions and warnings, the occurrence of NSF has dramatically decreased (i.e., virtual elimination) and no longer appears to be a major threat to patient health. This is an example of how close cooperation between manufacturers and regulators can successfully address a global safety issue. Other than differences in the number of spontaneous reports, there is no clear evidence to indicate that any one GBCA is more or less safe than any other with respect to NSF. The number of reports is confounded by multiple factors thus making it challenging to establish any basis to assess differential risk across the class of GBCAs. Unlike the Cox-2 inhibitor and cardiovascular safety issues, a lack of head-to-head comparison via adequate and wellcontrolled clinical trials makes differentiation between GBCAs more challenging.
49
We believe that post-marketing surveillance and structure/physical attributes do not provide a sufficient foundation for evidence-based conclusions regarding a differential risk profile for GBCAs. Overall, since class labeling was implemented in 2007, the safety profile for GBCAs, including Omniscan, has a positive benefit-risk ratio and does not necessitate further labeling actions to assure safe product use. Given product utilization in the marketplace for GBCAs and current labeling, it is our belief that careful assessment of all safety (not limited only to NSF) is crucial to assess benefit-risk for this class of agents. Additional communications to HCPs are warranted to assure that product use complies with approved professional product labeling.
50
10
REFERENCE LIST
Abraham JL, Thakral C, Skov L, Rossen K, Marckmann P. Dermal inorganic gadolinium concentrations: evidence for in vivo transmetallation and long-term persistence in nephrogenic systemic fibrosis. Br J Dermatol 2007. Agarwal R, Brunelli SM, Williams K, Mitchell MD, Feldman HI, Umscheid CA. Gadoliniumbased contrast agents and nephrogenic systemic fibrosis: a systematic review and metaanalysis. Nephrol Dial Transplant 2009; 24: 856863. American College of Radiology. Manual of Contrast Media. ACR.Org. 2008:v6:53-57. Bhagavathula N, DaSilva M, Aslam MN et al. Regulation of Collagen Turnover in Human Skin Fibroblasts Exposed to a Gadolinium-Based Contrast Agent. Investigative Radiology. 2009; 44: 433-439. Boyd AS et al. Gadolinium deposition in nephrogenic fibrosing dermopathy. J Am Acad Dermatol. 2007; 56: 27-30. Bridges MD, St. Amant BS, McNeil RB, Cernigliaro JG, Dwyer JP, Fitzpatrick PM. Highdose gadodiamide for catheter angiography and CT in patients with varying degrees of renal insufficiency: prevalence of subsequent nephrogenic systemic fibrosis and decline in renal function. Am J Roentgenol. 2009;192;1538-1543. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol 2007; 188(2):586-592. Cheng S, Abramova L, Saab G, Turabelidze G, Patel P, Arduino M et al. Nephrogenic Fibrosing Dermopathy Associated with Exposure to Gadolinium-Containing Contrast Agents. MMWR weekly . 2007. Ref Type: Electronic Citation. Cheng S et al. Nephrogenic fibrosing dermopathy associated with exposure to gadoliniumcontaining contrast agents St. Louis, Missouri, 2002-2006. JAMA 2007; 297: 1542-1544. Chen W, Huang SL, Huang CS, Tsai MC, Lai HM, Lui CC et al. Nephrogenic systemic fibrosis in advanced chronic kidney disease: A single hospital's experience in Taiwan. Eur J Dermatol 2008. Chrysochou C, Buckley D, Cowie A, Kalra PA. Gadolinium-Enhanced Magnetic Resonance Imaging for Renovascular Disease and Nephrogenic Systemic Fibrosis: Critical Review of the Literature and UK Experience. ASN 2008 Conference proceedings. 2009. ASN 2008. Collidge TA, Thomson PC, Mark PB, Traynor JP, Jardine AG, Morris ST, Simpson K, Roditi GH. Gadolinium-enhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort. Radiology. 2007; 245 (1): 168-75.
51
Cowper SE et al. Scleromyxoedema-like cutaneous diseases in renal dialysis patients. Lancet 2000; 356: 1000-1001. Cowper SE, Bucala R, LeBoit PE. Nephrogenic fibrosing dermopathy/nephrogenic systemic fibrosis setting the record straight. Semin Arthritis Rheum 2006; 35: 208-210. Cowper SE. Nephrogenic systemic fibrosis: a review and exploration of the role of gadolinium. Adv Dermatol 2007a; 23:131-154. Cowper SE. The International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR). Official site of the Nephrogenic Fibrosing Dermopathy (NFD/NSF) Registry. Accessed 27 March 2007b. Cowper SE. The International Center for Nephrogenic Fibrosing Dermopathy Research (ICNFDR). Official site of the Nephrogenic Fibrosing Dermopathy (NFD/NSF) Registry , 1-6. 27-3-2007b. Ref Type: Electronic Citation Cowper SE. Nephrogenic fibrosing dermopathy [NFD/NSF Website]. 2001-2007. Available at http://www.icnfdr.org. Accessed 3 November 2008. DeHoratius DM, Cowper SE. Nephrogenic systemic fibrosis: an emerging threat among renal patients. Semin Dial 2006; 19: 191-194. Del Galdo F, Wermuth P, Jimenez SA. Activation of Toll-like Receptor Pathways and Induction of Chemokine Production in Normal Human Macrophages by a gadolinium Containing Contrast Agent: Trigger Event in the Pathogenesis of Nephrogenic Systemic Fibrosis? Abstract 1803. ACR Congress 2008. Arthritis Rheum. 2008; 58: S831. Deng AC, Bilu DM, Sina B, Gaspari A. Localized nephrogenic fibrosing dermopathy: Aberrant dermal repairing; J Am Acad Dermatol 2008; 58(2):336-339. Deo A, Fogel M, Cowper SE. Nephrogenic systemic fibrosis: a population study examining the relationship of disease development to gadolinium exposure. Clin J Am Soc Nephrol. 2007; 2:264-7. Edward M, Quinn JA, Mukherjee S, Jensen, M-BV, Jardine AG, Mark PB and Burden AD. Contrast agent 'activates' fibroblasts: a possible cause of nephrogenic systemic fibrosis. J Pathol. 2008; 214 (5): 584-593. Elmsthl B, Leander P, Grant D, Doughty RW, Chai CM, Bjork J et al. Histomorphological Changes after Renal X-Ray Arteriography Using Iodine and Gadolinium Contrast Media in an Ischemic Porcine Model. Acta Radiol 2007; 1-11. Franano FN, Edwards WB, Welch MJ, Brechbiel MW, Gansow OA and Duncan JR. Biodistribution and metabolism of targeted and nontargeted protein-chelate-gadolinium complexes: evidence for gadolinium dissociation in vitro and in vivo. Mag Res Imag. 1995; 13(2): 201-214.
52
Frenzel T, Lengsfeld P, Schirmer H, Htter J, Weinmann HJ. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol. 2008; 43:817828. Gibby WA et al. Comparison of Gd DTPA-BMA (Omniscan) versus Gd HP-DO3A (ProHance) retention in human bone tissue by inductively coupled plasma atomic emission spectroscopy. Invest Radiol 2004; 39: 138-142. Grant D, Johnsen H. Juelsrud A. Lovhaug. Effects of Gadolinium Contrast Agents in Nave and Nephrectomized Rats: Relevance to Nephrogenic Systemic Fibrosis, Acta Radiologica. 2009; 21:1-14. Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Nephrol Dial Transplant 2006; 21(4):11041108. Grobner T. Gadolinium--a specific trigger for the development of nephrogenic fibrosing dermopathy and nephrogenic systemic fibrosis? Reply. Nephrol Dial Transplant 2006; 1745. Harpur ES, Worah D, Hals PA, Holtz, E, Furuhama K, Nomura H. Preclinical safety assessment and pharmacokinetics of gadodiamide injection, a new magnetic resonance imaging contrast agent. Invest Radiol. 1993;28 Suppl 1:S28-S43. Heinz-Peer G, Neruda A, Watschinger B, Vychytil A, Geusau A, Haumer M et al. Prevalence of NSF following intravenous gadolinium-contrast media administration in dialysis patients with endstage renal disease. Eur J Radiol 2009. Herlenius G, Fistouris J, Olausson M, Felldin M, Backman L, Friman S. Early renal function post-liver transplantation is predictive of progressive chronic kidney disease. Scand J Gastroenterol 2008; 43(3):344-349. High WA, Ayers RA, Chandler J, Zito G, Cowper SE. Gadolinium is detectable within the tissue of patients with nephrogenic systemic fibrosis. J Am Acad Dermatol Nov, 2007. Hoppe H, Spagnuolo S, Froehlich JM, Nievergelt H, Dinkel HP, Gretener S et al. Retrospective analysis of patients for development of nephrogenic systemic fibrosis following conventional angiography using gadolinium-based contrast agents. Eur Radiol 2009. Hunt CH, Hartman RP, Hesley GK. Frequency and Severeity of Adverse Effects of Iodinated and Gadolinium Contrast Materials: Retrospective review of 456,930 Doses. AJR 2009;193:1124-1127. Ide JM, Port M, Raynal I, Schaefer M, Le Greneur S, Corot C. Clinical and biological consequences of transmetallation induced by contrast agents for magnetic resonance imaging: a review. Fundam. Clin. Pharmacol 2006; 20: 563-76. Erratum in: Fundam. Clin. Pharmacol. 2007; 21: 335.
53
Issa N et al. Nephrogenic systemic fibrosis and its association with gadolinium exposure during MRI. Cleve Clin J Med 2008; 75: 95-111. Janus N, Launay-Vacher V, Karie S, Clement O, Ledneva E, Frances C et al. Prevalence of nephrogenic systemic fibrosis in renal insufficiency patients: Results of the FINEST study. Eur J Radiol 2009; In Press, Corrected Proof. Jain SM, Wesson S, Hassanein A, Canova E, Hoy M, Fennell RS et al. Nephrogenic fibrosing dermopathy in pediatric patients. Pediatr Nephrol 2004; 19(4): 467-470. Jimenez SA, Artlett CM, Sandorfi N, Derk C, Latinis K, Sawaya H, Haddad R and Shanahan JC. Dialysis-associated systemic fibrosis (nephrogenic fibrosing dermopathy): study of inflammatory cells and transforming growth factor beta1 expression in affected skin. Arthritis Rheumatology. 2004; 50: 26602666. Joffe P, Thomsen HS, Meusel M. Pharmacokinetics of gadodiamide injection in patients with severe renal insufficiency and patients undergoing hemodialysis or continuous ambulatory peritoneal dialysis. Academic Radiology. 1998;5:491502. Kadiyala D, Roer DA, Perazella MA. Nephrogenic systemic fibrosis associated with gadoversetamide exposure: treatment with sodium thiosulfate. Am J Kidney Dis 2009; 53(1):133-137. Kallen AJ, Jhung MA, Cheng S, Hess T, Turabelidze G, Abramova L et al. Gadoliniumcontaining magnetic resonance imaging contrast and nephrogenic systemic fibrosis: a casecontrol study. Am J Kidney Dis 2008; 51(6):966-975. Kuo PH, Kanal E, Abu-Alfa AK, Cowper SE. Gadolinium-based MR contrast agents and nephrogenic systemic fibrosis. Radiology. 2007; 242 (3): 647-9. Kuo PH. NSF Active and NSF-Inert Species of Gadolinium: Mechanistic and Clinical Implications. American Journal of Radiology. 2008; 191: 1861-1863. Lauenstein TC, Salman K, Morreira R, Tata S, Tudorascu D, Baramidze G et al. Nephrogenic systemic fibrosis: Center case review. J Magn Reson Imaging 2007; 26(5):1198-1203. Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003; 139(2):137-147. Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG et al. Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging. J Am Soc Nephrol 2006; 17:2359-2362. Marckmann P, Skov L, Rossen K, Thomsen HS. Clinical manifestation of gadodiamide-related nephrogenic systemic fibrosis. Clin Nephrol 2008a; 69(3):161-168.
54
Marckmann P. An epidemic outbreak of nephrogenic systemic fibrosis in a Danish Hospital. Eu J Radiol. 2008b; 66(2):187-190. Mendoza FA et al. Description of twelve cases of nephrogenic fibrosingdermopathy and review of the literature. Sem Arthritis Rheum 2006; 35:238-249. Morris MF, MacGregor J, Zhang H, Grossman M, Silvers D, Valeri A, Silberzweig J, Kapoor R, McNutt N and Prince MR. Factors relating to development of Nephrogenic Systemic Fibrosis following Gadolinium. Proc. Intl. Soc. Mag. Reson. Med. 15 (2007) 739 Abstract: A retrospective case-control study of gadolinium-enhanced magnetic resonance imaging and nephrogenic systemic fibrosis in patients with renal failure. 07 Mar 9; 2007. Murphy KP, Szopinski KT, Cohan RH, Mermillod B, Ellis JH. Occurrence of adverse reactions to gadolinium-based contrast material and management of patients at increased risk: a survey of the American Society of Neuroradiology Fellowship Directors. Acad Radiol 1999; 6:656664. National Kidney Foundation. K/DOQI clinical practice guidelines for chronic kidney disease: Evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 2002; 39(suppl 1): S1-S266. Nelson KL, Gifford LM, Lauber-Huber C, Gross CA, Lasser TA. Clinical safety of gadopentetate dimeglumine. Radiology 1995;196:439-443. Nephrogenic systemic fibrosis: risk factors and incidence estimation. Radiology 2007;243:148157. Newton BB, Jimenez SA, Mechanism of NSF: New Evidence Challenging the Prevailing Theory JMRI 2009 In press. Niendorf HP, Haustein J, Cornelius I, Alhassan A, Clauss W. Safety of gadolinium DTPA: extended clinical experience. Magn Reson Med 1991;22:222-228. Nyman U, Elmstahl B, Leander P. Suggesting gadolinium-based contrast media for CT in azotemic patients is not based on historical, clinical, and experimental data. Radiology 2007; 244(2):622-623. Nyman U, Elmstahl B, Nilsson M. The dogma that gadolinium contrast media are less nephrotoxic than iodine agents for X-ray angiography is a misconception. Heart Vessels 2007; 22(3):211-212. Othersen JB, Maize JC, Woolson RF, Budisavljevic MN. Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure. Nephrol Dial Transplant 2007; 22(11):3179-3185. Perazella MA. Gadolinium-contrast toxicity in patients with kidney disease: nephrotoxicity and nephrogenic systemic fibrosis. Curr Drug Saf. 2008; 3:67-75.
55
Pietsch H, Lengsfeld P, Jost G, Frenzel T. Htter J, Sieber MA. Long-term retention of gadolinium in the skin of rodents following the administration of gadolinium-based contrast agents. Eur Radiol 2009;19(6):1417-24. Prince, MR, Zhang H, Morris M, MacGregor J, Grossman M, Silberzweig J, DeLapaz RL, Lee HJ, Magro CM, Valeri AM. Incidence of Nephrogenic Systemic Fibrosis at Two Large Medical Centers. Radiology. 2008; 248: 807-816. Pryor J, Poggioli G, Galaria N, Gust A, Robison J, Samie F, Hanjani N, Scott G. Nephrogenic systemic fibrosis: A clinicopathologic study of six cases. Journal of the American Academy of Dermatology, 2008; Volume 57, Issue 1, Pages 105-111. Reilly RF. Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long-term hemodialysis. Clin J Am Soc Nephrol 2008; 3(3):747-751. Rydahl C, Thomsen HS, Marckmann P. High Prevalence of Nephrogenic Systemic Fibrosis in Chronic Renal Failure Patients Exposed to Gadodiamide, a Gadolinium-Containing Magnetic Resonance Contrast Agent. Invest Radiol 2008; 43(2):141-144. Sadowski EA, Bennett LK, Chan M, Wentland AL, Garrett AL, Garrett RW, et al. Nephrogenic Systemic Fibrosis: Risk Factors and Incidence Estimation. Radiology 2007; 243(1):148-157. Salman KN, Moreira R, Sharma P, Tudorascu D, Holder C, Martin DR. Evaluation of a Possible Risk Association between Nephrogenic Sclerosing Dermopathy (NFD) and Gadolinium Enhanced MRI. Proc Intl Soc Magn Res Med 2007; 15:742. Shenoy C. Gadolinium-induced nephrogenic systemic fibrosis in patients with kidney and liver disease. Am J Med 2008; 121(1):e11. Sieber MA, Lengsfeld P, Frenzel T, Golfier S, Schmitt-Willich H, Siegmund F, Walter J, Weinmann HJ, Pietsch H. Preclinical investigation to compare different gadolinium-based contrast agents regarding their propensity to release gadolinium in vivo and to trigger nephrogenic systemic fibrosis-like lesions. Eur Radiol 2008b;18(10): 2164-73. Sieber MA, Pietsch H, Walter J, Haider W, Frenzel T, Weinmann HJ. A preclinical study to investigate the development of nephrogenic systemic fibrosis: a possible role for gadoliniumbased contrast media. Invest Radiol. 2008a; 43:6575. Staks T, Schumann-Giampieri G, Frenzel T et al., Pharmacokinetics, dose proportionality, and tolerability of gadobutrol after single intravenous injection in healthy volunteers, Investigative Radiology. 1994;29:709715. Swaminathan S, Ahmed I, McCarthy JT, Albright RC, Pittelkow MR, Caplice NM et al. Nephrogenic fibrosing dermopathy and high-dose erythropoietin therapy. Ann Intern Med. 2006; 145(3):234-235.
56
Swaminathan S, Horn TD, Pellowski D, Abul-Ezz S, Bornhorst JA, Viswamitra S et al. Nephrogenic systemic fibrosis, gadolinium, and iron mobilization. N Engl J Med. 2007b; 357(7):720-722. Swaminathan S, Shah SV. New insights into nephrogenic systemic fibrosis. J Am Soc Nephrol. 2007a; 18: 2636-2643. Thakral C, Abraham JL. Automated Scanning Electron Microscopy and X-Ray Microanalysis for in situ Quantification of Gadolinium Deposits in Skin. J Elec Micro. 56(5): 181-187, 2007. Thomsen HS. Nephrogenic systemic fibrosis: a serious late adverse reaction to gadodiamide. Eur Radiol 2006; 16: 2619-2621. Ting WW, Stone MS, Madison KC, Kurtz K. Nephrogenic fibrosing dermopathy with systemic involvement. Arch Dermatol 2003; 139(7):903-906. Todd DJ, Kagan A, Chibnik LB, Kay J. Cutaneous changes of nephrogenic systemic fibrosis: Predictor of early mortality and association with gadolinium exposure. Arthritis Rheum 2007; 56(10):3433-3441. Tombach B, Bremer C, Reimer P et al. Pharmacokinetics of 1M Gadobutrol in Patients with Chronic Renal Failure. Investigative Radiology. 2000;35:35-40. Townsend RR Cohen DL, Katholi R et al. Safety of intravenous gadolinium (Gd-BOPTA) infusion in patients with renal insufficiency. American Journal of Kidney Disease. 2000;36:12071212. Varani J, DaSilva M, Warner RL, OBrien MD, Barron AG, Johnson KJ, Swartz R. Effects of gadolinium-Based MRI Contrast Agents on Human Skin in Organ Culture and Human Skin Fibroblasts. Investigative Radiology. 2009; 44 (2): 74-81. Wahba IM, Simpson EL, White K. Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature. Am J Transplant 2007; 7(10):2425-2432. Wermuth PJ, Del Galdo F, Jimnez SA. Induction of expression of profibrotic/proinflammatory proteins in normal human peripheral blood mononuclear cells (PBMC). Role in Pathogenesis of gadolinium-Associated Nephrogenic Systemic Fibrosis. Abstract FRI0259. EULAR 2008. Ann Rheum Dis. 2008; 67 (suppl II): 366. Wermuth PJ, Del Galdo F, Jimnez SA. Induction of the Expression of Profibrotic Cytokines and Growth Factors in Normal Human Peripheral Blood Monocytes by Gadolinium Contrast Agents. Arthritis and Rheumatism. 2009a; 60: 1508-1518. Wermuth PJ, Del Galdo F, Jimenez, SA. 2009. Induction of Expression of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents. Arthritis Rheum. 2009b; 60(5): 1508-18.
57
Wertman R, Altun E, Martin DR, Mitchell DG, Leyendecker JR, O'Malley RB et al. Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American universities. Radiology 2008; 248(3):799-806. White GW et al. Comparison of Gd (DTPA-BMA) (Omniscan) versus Gd(HP-DO3A) (ProHance) relative to gadolinium retention in human bone tissue by inductively coupled plasma mass spectroscopy. Invest Radiol 2006;41: 273-278. Wiginton CD, et al. Gadolinium-based contrast exposure, nephrogenic systemic fibrosis and gadolinium detection in tissue. Am J Roentgenol. 2008; 190(4): 1060-1068. Wollanka H, Weidenmaier W, Giersig C. NSF after Gadovist exposure: a case report and hypothesis of NSF development. Nephrol Dial Tranplant 2009. In press. Zhang H, Morris M et al. Incidence of Nephrogenic Systemic Fibrosis at Two Large Medical Centers. Radiology. 2008;248:807-816.
58
APPENDIX A
ABSTRACTS
Abstracts from Tables 9 and 10 [See Omniscan Briefing document [Section 5.2.2] Bridges MD, St Amant BS, McNeil RB, Cernigliaro JG, Dwyer JP, Fitzpatrick PM. High-dose gadodiamide for catheter angiography and CT in patients with varying degrees of renal insufficiency: Prevalence of subsequent nephrogenic systemic fibrosis and decline in renal function. AJR Am J Roentgenol 2009; 192(6):1538-1543. OBJECTIVE: The purpose of our study was to evaluate the prevalence of nephrogenic systemic fibrosis (NSF) and nephrotoxicity among patients with differing degrees of renal dysfunction who are exposed to high doses of gadodiamide. MATERIALS AND METHODS: A search of medical records identified patients who received high-dose IV gadodiamide for catheter angiography or CT between January 2002 and December 2005. The cohort was limited to patients who had received a dose of at least 40 mL of gadodiamide during a single imaging session, who underwent at least 1 year of clinical follow-up, and who had moderate to end-stage renal disease (estimated glomerular filtration rate [GFR] < 60 mL/min/1.73 m(2)) established within the previous 48 hours. Any observation suggestive of NSF was recorded, as were all estimated GFR values obtained during the 2 weeks before and the 5 days after gadodiamide administration. RESULTS: Sixty-one patients met the inclusion criteria. The median estimated GFR was 30 mL/min/1.73 m(2) (range, 3-57 mL/min/1.73 m(2)). The median gadodiamide exposure was 80 mL (range, 40-200 mL). NSF eventually developed in one of the 61 patients, yielding a prevalence of 1.6%. Among the 33 patients not undergoing dialysis with estimated GFR documented within 5 days after contrast injection, the change in estimated GFR ranged from 8.8 to 42.9 mL/min/1.73 m(2), with a statistically significant median improvement of 2.4 mL/min/1.73 m(2) (p = 0.007). CONCLUSION: Although gadolinium exposure appears to be a necessary precondition for NSF, gadolinium-based contrast agents alone are not sufficient to cause the disorder, even in very high doses. Clinically relevant nephrotoxicity of gadolinium-based contrast agents was not found. Broome DR, Girguis MS, Baron PW, Cottrell AC, Kjellin I, Kirk GA. Gadodiamide-associated nephrogenic systemic fibrosis: why radiologists should be concerned. AJR Am J Roentgenol 2007; 188(2):586-592. OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a rare multisystemic fibrosing disorder that principally affects the skin but may affect other organs of patients with renal insufficiency. The purpose of our study was to identify any common risk factors and determine whether i.v. gadodiamide is associated with the development of NSF.
A-1
MATERIALS AND METHODS: A retrospective chart review was performed for all 12 patients diagnosed with NSF at our institution between 2000 and 2006 to identify the clinical manifestations, timing, and dose of gadodiamide administration; dialysis records; concurrent medications; comorbid conditions and surgeries; laboratory findings; imaging findings; and clinical outcome. A review of the dialysis and MR records between 2000 and 2006 showed 559 MRI examinations on 168 dialysis patients (including 301 contrast-enhanced examinations). RESULTS: NSF was diagnosed by clinical findings and tissue diagnosis. All 12 patients had renal insufficiency--eight with dialysis-dependent chronic renal insufficiency and four with acute hepatorenal syndrome. All 12 patients developed skin fibrosis within 2-11 weeks after gadodiamide administration. The odds ratio for development of NSF after gadodiamide exposure was 22.3. No other common event or exposure could be found. Four patients had abnormal scintigraphic bone scans with skin and muscle uptake and lower-extremity MRI finding of edema in the muscles, intermuscular fascia, and skin. Despite the fact that 10 patients were dialyzed within 2 days of gadodiamide administration, this did not prevent the development of NSF. CONCLUSION: Development of NSF was strongly associated with gadodiamide administration in the setting of either acute hepatorenal syndrome or dialysis-dependent chronic renal insufficiency. Cheng S, Abramova L, Saab G, Turabelidze G, Patel P, Arduino M et al. Nephrogenic Fibrosing Dermopathy Associated with Exposure to Gadolinium-Containing Contrast Agents. MMWR weekly . 2007. Ref Type: Electronic Citation Chen W, Huang SL, Huang CS, Tsai MC, Lai HM, Lui CC et al. Nephrogenic systemic fibrosis in advanced chronic kidney disease: A single hospital's experience in Taiwan. Eur J Dermatol 2008. Abstract: Nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD) clinically resembles scleromyxedema which develops in the setting of advanced chronic kidney diseases. Limited data exist about its epidemiology in Asian countries. A total of 153 magnetic resonance imaging (MRI) examinations, including 81 contrast-enhancement, were identified in 127 patients with advanced chronic kidney disease at stage five undergoing MRI or angiography examination between January 2005 and July 2007, in our hospital. The diagnosis of NFD/NSF was established based on clinical manifestation and histopathology. NFD/NSF was diagnosed in none of the 105 patients on haemodialysis but in one of the 22 patients on peritoneal dialysis. This 24-year-old woman was a case of systemic lupus erythematosus since age 15 and who developed skin lesions two months before the initiation of peritoneal dialysis but nine months after four exposures to gadodiamide during MRI study. The skin condition had significantly improved within three months under a combination regimen of systemic pentoxifylline and topical clobetasol propionate ointment, with further amelioration during subsequent treatment with colchicine. Our results lend support to the predisposition of gadolinium-containing contrast agents to the development of NFD/NSF in patients with advanced renal failure, even before the initiation of dialysis. The cause of a lower incidence rate in our series remains to be determined.
A-2
Chrysochou C, Buckley D, Cowie A, Kalra PA. Gadolinium-Enhanced Magnetic Resonance Imaging for Renovascular Disease and Nephrogenic Systemic Fibrosis: Critical Review of the Literature and UK Experience. ASN 2008 Conference proceedings. 2009. ASN 2008. Ref Type: Abstract Abstract: Nephrogenic systemic fibrosis (NSF) is a newly described, rare but potentially devastating condition. The link with gadolinium (Gd) exposure in patients with severe renal impairment has impacted strongly on international radiology safety guidelines. We believe not all patients with a GFR <30ml/min should be regarded as high risk. Methods 1. We conducted a literature search to obtain critical review on the existing literature on NSF. 2. We contrasted this with our centres experience of all patients undergoing MRA since 1999. 3. All participating centres of the multicentre ASTRAL trial were contacted to assess whether any patients screened or enrolled into ASTRAL had developed NSF. Results: Critical review of the literature reveals that almost all NSF cases have occurred in patients with CKD5 on or close to dialysis, unstable renal function, or in those receiving multiple Gd doses. At our centre, 562 patients were available for follow up (median follow up 28 months). Median age 69 years (range 21-93). 92.7% received Magnevist, 6.5% Omniscan and 0.8% Vasovist. 30% were CKD4, 15% CKD5, 5% on dialysis and 0.2% transplanted at the time of imaging. 26 CKD4 or 5 patients had two MRA s. No patients developed any signs or symptoms of NSF. 45 /58 participating ASTRAL centres responded to our enquiry. 347 patients (mean eGFR 40ml/min, 32% CKD4 or 5) were enrolled into ASTRAL on the basis of MRA. One of these patients (CKD5, received 2 Gd scans) developed NSF. Approximately 5 times as many patients were screened as were entered into ASTRAL. Conclusion: No cases of NSF were observed in 562 (45% CKD 4 or 5) patients investigated at our centre. By extrapolation, 1/1735 patients screened for the ASTRAL trial developed NSF, giving a crude incidence rate of 0.06%. We would argue that patients with CKD4 can safely undergo Gd-MRA, albeit using half the standard dose of a macrocyclic (as opposed to linear characteristic) Gd containing agent and avoiding repeat doses.
Collidge TA, Thomson PC, Mark PB, Traynor JP, Jardine AG, Morris ST et al. Gadoliniumenhanced MR imaging and nephrogenic systemic fibrosis: retrospective study of a renal replacement therapy cohort. Radiology 2007; 245(1):168-175. PURPOSE: To retrospectively compare the frequency of administration and cumulative dose of gadolinium-based contrast agent in dialysis-dependent patients who did and those who did not develop nephrogenic systemic fibrosis.
A-3
MATERIALS AND METHODS: The ethics committees granted exempt status for this study and also waived the need for informed consent. A retrospective analysis was performed of all adult patients undergoing dialysis in the west of Scotland between January 1, 2000, and July 1, 2006. Diagnoses of nephrogenic systemic fibrosis, episodes of gadolinium-enhanced magnetic resonance (MR) imaging, and cumulative doses of gadolinium-based contrast agent were recorded. Outcomes were analyzed by means of parametric and nonparametric testing. RESULTS: Fourteen of 1826 patients had a diagnosis of nephrogenic systemic fibrosis. Mortality was similar for affected and nonaffected patients. Thirteen (93%) of 14 patients with nephrogenic systemic fibrosis had undergone gadolinium-enhanced MR imaging compared with 408 (22.5%) of 1812 nonaffected patients (P<.001). Patients with nephrogenic systemic fibrosis received a higher median cumulative dose of gadodiamide (0.39 vs 0.23 mmol per kilogram of body weight, P=.008) and underwent more gadolinium-enhanced MR imaging than their nonaffected gadolinium-exposed counterparts. CONCLUSION: The data support a positive association between gadolinium-based contrast agent administration and development of nephrogenic systemic fibrosis in the established renal failure population; in addition, there is a positive association between cumulative dose of gadodiamide used and dosing events.
Cowper SE, Robin HS, Steinberg SM, Su LD, Gupta S, LeBoit PE. Scleromyxoedema-like cutaneous diseases in renal-dialysis patients. Lancet 2000; 356(9234):1000-1001. Abstract: 15 renal dialysis patients have been identified with a skin condition characterised by thickening and hardening of the skin of the extremities and an increase in dermal fibroblastlike cells associated with collagen remodelling and mucin deposition. The disease closely resembles scleromyxoedema, yet has significant enough clinical and histopathological differences to warrant its designation as a new clinicopathological entity.
Cowper SE. Nephrogenic systemic fibrosis: a review and exploration of the role of gadolinium. Adv Dermatol 2007a; 23:131-154. Abstract: NSF is a new and emerging disease. Significant investigative work to date has led to an unexpected suspect-gadolinium-containing contrast agents. Considerable additional work is now underway to formulate specific recommendations about the use of these agents in the population of patients who have renal disease. Goals on the immediate research horizon include (1) the identification of risk factors and conditions that must be met to permit the development of NSF in patients who have renal disease, (2) the characteristics of contrast agents that make them more or less likely to induce NSF, and (3) the development of prophylactic or treatment strategies that can reduce the overall development and severity of NSF. The investigative process has already yielded new insight into the functions (and malfunctions) of the CF in the setting of NSF. As the CF is being increasingly implicated in other organ-specific and systemic fibrosing disorders, we can expect to see significant developments in the studies of allied disorders as well.
A-4
Deng AC, Bilu DM, Sina B, Gaspari A. Localized nephrogenic fibrosing dermopathy: Aberrant dermal repairing; J Am Acad Dermatol 2008; 58(2):336-339. Abstract: Nephrogenic fibrosing dermopathy (NFD) has emerged as a clinicopathologic entity since 2000 and was recently renamed nephrogenic systemic fibrosis. The cause and pathogenesis remain uncertain. The classic clinical presentation is diffuse thickening and hardening of the skin that occurs in patients with renal insufficiency, with or without systemic involvement. We report a patient with renal failure who presented to our dermatology clinic with a localized plaque on the left forearm along the vein that was traumatized during the infusion of erythropoietin. Histologic examination revealed a dermal proliferation of CD34(+) fibrocytes with collagen fibers and interstitial mucin accumulation, features characteristic for NFD. We conclude that NFD may present as a localized, scarlike plaque after trauma and exhibit overlapping histopathologic features resembling cicatrix and other dermal reparative/regenerative processes. NFD may, in fact, be a disorder of aberrant extracellular matrix remodeling in patients with renal insufficiency. This is a single case observation with discussion of literature and attempted hypothesis on pathogenesis. No experimental evidence is provided.
Deo A, Fogel M, Cowper SE. Nephrogenic Systemic Fibrosis: A Population Study Examining the Relationship of Disease Development to Gadolinium Exposure. Clin J Am Soc Nephrol 2007;CJN. Abstract: Nephrogenic systemic fibrosis (NSF) is a devastating complication of severe renal failure. Recent reports suggest that exposure to gadolinium-containing contrast agents (GCCA) is associated with the occurrence of NSF. The population of patients with ESRD in and around Bridgeport, CT, was studied during an 18-mo period. The incidence of NSF was 4.3 cases per 1000 patient-years. Each radiologic study using gadolinium presented a 2.4% risk for NSF. The association between gadolinium exposure and NSF was highly significant (P [≤] 0.001). It is concluded that GCCA exposure is a major risk factor for NSF in the ESRD population. Because of the significant morbidity and mortality with NSF, it is believed that gadolinium exposure should be avoided in patients with ESRD. In the event that exposure cannot be avoided, careful consideration of the potential consequences, including a thorough discussion of the risks and benefits of GCCA, is advised.
Elmsthl B, Leander P, Grant D, Doughty RW, Chai CM, Bjork J et al. Histomorphological Changes after Renal X-Ray Arteriography Using Iodine and Gadolinium Contrast Media in an Ischemic Porcine Model. Acta Radiol 2007;1-11. Background: Gadolinium contrast media (Gd-CM) are regarded as non-nephrotoxic or considerably less nephrotoxic than iodine contrast media (I-CM), and have therefore come to
A-5
be used as a substitute for I-CM in patients with renal insufficiency in a variety of radiographic examinations. Purpose: To investigate renal histomorphological changes caused by Gd-CM in comparison with I-CM after renal X-ray arteriography in an ischemic porcine model, and to evaluate these changes in relation to the nephrotoxicity of the CM used. Material and Methods: Test solutions: gadopentetate, gadodiamide, iohexol, gadobutrol, iopromide, iodixanol, mannitol, and saline. The experiments were performed on 152 animals. Each pig was randomized to receive one test solution injected into the balloon-occluded (10 min) right renal artery. The kidneys were evaluated histomorphologically. The severity of histomorphological changes was graded subjectively: 1 = minimal, 2 = mild, 3 = moderate, and 4 = marked. Results: The main histological changes were 1) proximal tubular and glomerular necrosis, 2) hemorrhage/congestion of the cortex, medulla, and glomeruli, 3) proximal tubular vacuolation, and 4) protein-filled tubules in the cortex and medulla. Necrosis and hemorrhage/congestion were more frequent after injections with gadopentetate, mannitol solution iso-osmotic to gadopentetate, and gadobutrol compared to all other groups (P<0.001). The degree of necrosis and hemorrhage/congestion was related to the degree of impairment of renal function, but inversely related to vacuolation and tubular protein filling. Conclusion: In ischemic porcine kidneys, the histomorphological changes caused by Gd-CM are similar to those caused by I-CM. Vacuolation appears to be independent of the osmolality and viscosity of the CM, and does not seem to be an indicator of renal impairment. "Highosmolal" Gd-CM are more nephrotoxic than "low- and iso-osmolal" I-CM when compared in equal volumes of concentrations, resulting in equal X-ray attenuation.
FDA. Gadolinium-Based Contrast Agents for Magnetic Resonance Imaging (marketed as Magnevist, MultiHance, Omniscan, OptiMARK, ProHance). 23-5-2007. Ref Type: Internet Communication Abstract: pplyBrkRulesFDA 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 gadoliniumbased 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 <30 mL/min/1.73m2) and patients with acute renal insufficiency of any severity due to the hepatorenal 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 noncontrast enhanced magnetic resonance imaging. NSF may result in fatal or debilitating systemic fibrosis. Requested changes to GBCA product labeling are summarized below.
A-6
Heinz-Peer G, Neruda A, Watschinger B, Vychytil A, Geusau A, Haumer M et al. Prevalence of NSF following intravenous gadolinium-contrast media administration in dialysis patients with endstage renal disease. Eur J Radiol 2009. Abstract: PURPOSE: To evaluate the prevalence of nephrogenic systemic fibrosis (NSF) in a patient population being at highest risk for developing this disease and to evaluate possible risk factors. MATERIALS AND METHODS: The radiological records of 552 patients with ESRD being on hemodialysis (HD) or peritoneal dialysis (PD) were retrospectively reviewed to identify whether the patients underwent MR-examinations with or without intravenous administration of GBCA. In case of exposure to GBCA, the number of contrast injections, the benchmark and the cumulative doses of GBCA, and possible cofactors regarding pathogenesis of NSF were recorded. Diagnosis of NSF was confirmed either by deep skin biopsy or by review of medical and histopathological records. Data of NSF patients were compared with data of dialysis patients who did not develop NSF after MR-examinations. RESULTS: 146 dialysis patients underwent MRI without i.v.-administration of GBCA. No case of NSF was observed in this patient population. 195/552 patients proved to have a total number of 325 well-documented exposures to GBCA. Seven different types of GBCA were used during these MR-examinations. NSF prevalence rate was 1.6%. One patient died of NSF. Three different types of GBCA were involved in 6 NSF cases. 4/6 proved to be confounded cases. The cumulative dose of GBCA, history of thrombosis, recent surgery, and the combination of HD and PD proved to be significant cofactors for the development of NSF (p<.05). No significant difference regarding residual renal clearance (p=.898) and residual urine volume (p=.083) was found between NSF and non-NSF patients. CONCLUSION: The prevalence of NSF proved to be much lower in this high risk patient group being exposed to GBCA compared to the literature. NSF was not observed in ESRD patients undergoing MRI without administration of GBCA. Our data support a positive association between cumulative dose of GBCA and development of NSF. No positive association was found between residual renal clearance and residual urine volume and NSF.
Herlenius G, Fistouris J, Olausson M, Felldin M, Backman L, Friman S. Early renal function post-liver transplantation is predictive of progressive chronic kidney disease. Scand J Gastroenterol 2008; 43(3):344-349. OBJECTIVE: With improvements in long-term results after liver transplantation, chronic kidney disease (CKD) has become a highly relevant problem. The early measurement of the glomerular filtration rate (GFR) can identify those patients who are at risk of developing CKD years after liver transplantation. The aims of this study were to describe the prevalence of CKD
A-7
5 years after liver transplantation, to study the correlation between measured GFR early after transplantation and late renal function and to identify patients at risk of developing late CKD after liver transplantation. MATERIAL AND METHODS: A total of 152 patients who were at least 5 years post-liver transplantation were studied. Measured GFR with Chromium EDTA or iohexol clearance was followed-up for 5 years (n 52) and 10 years (n 41). RESULTS: The overall decrease in measured GFR was 36% after 5 years and 42% after 10 years. Eight patients (5%) required renal replacement therapy. GFR levels pretransplantation showed a poor correlation with later renal function (at 5 years). The GFR measured at 3 months and 1 year post-transplantation correlated well with measured GFR at 5 years posttransplantation. Multivariate analysis showed that measured GFR of less than 30 ml at 3 months post-transplantation was significantly associated with CKD at 5 years posttransplantation. CONCLUSIONS: GFR levels below 30 ml/min/1.73 m2 at 3 months post-liver transplantation are associated with the development of later CKD Stage 4-5 long after liver transplantation. The importance of this finding is the possibility of identifying at an early stage those individuals that may benefit from early implementation of calcineurin sparing or a withdrawal regimen with the goal of preserving long-term renal function.
Hoppe H, Spagnuolo S, Froehlich JM, Nievergelt H, Dinkel HP, Gretener S et al. Retrospective analysis of patients for development of nephrogenic systemic fibrosis following conventional angiography using gadolinium-based contrast agents. Eur Radiol 2009. PURPOSE: The purpose was to retrospectively review the data of 27 patients with renal insufficiency who underwent conventional angiography with gadolinium-based contrast agents (GDBCA) as alternative contrast agents and assess the occurrence of nephrogenic systemic fibrosis (NSF) together with associated potential risk factors. METHODS: This HIPAA-compliant study had institutional review board approval, and informed consent was waived. Statistical analysis was performed for all available laboratory and clinical data, including dermatology reports. Type and amount of the GDBCA used were recorded for angiography and additional MRI studies, if applicable. Serum creatinine levels (SCr) pre- and post-angiography were recorded, and estimated glomerular filtration rates (eGFR) were calculated. RESULTS: Ten female and 17 male patients who underwent angiography with GDBCA were included. The mean amount of GDBCA administered was 44 +/- 15.5 ml (range 15-60 ml) or 0.24 + 0.12 mmol/kg (range 0.1-0.53 mmol/kg). At the time of angiography all patients had renal insufficiency (eGFR <60 ml/min/1.73 m(2)). Mean eGFR pre-angiography was 26 ml/min/1.73 m(2) and 33 ml/min/1.73 m(2) post-angiography. The mean follow-up period covers 28 months, range 1-84 months. Additional MRI studies with GDBCA administration
A-8
were performed in 15 patients. One patient with typical skin lesions had developed biopsyconfirmed NSF. CONCLUSION: Conventional arterial angiography with GDBCA may play a role in the development of NSF in patients with renal insufficiency. Alternative contrast agents, such as CO(2) angiography or rather the use of low doses of iodinated contrast agents, should be considered in these patients.
Janus N, Launay-Vacher V, Karie S, Clement O, Ledneva E, Frances C et al. Prevalence of nephrogenic systemic fibrosis in renal insufficiency patients: Results of the FINEST study. Eur J Radiol 2009; In Press, Corrected Proof. Purpose Nephrogenic systemic fibrosis (NSF) is characterized by widespread tissue fibrosis, mainly affecting the skin. Gadolinium chelates have been implicated in the onset of NSF in patients with renal impairment (RI). The FINEST study (FIbrose Nqphrogqnique SysTqmique) was designed to determine the prevalence of NSF after magnetic resonance imaging (MRI) in French RI patients. Materials and methods We studied all patients with RI who had at least one MRI examination during a one-year period, with or without gadolinium chelate administration. Data were collected retrospectively from 9 Nephrology Departments in France, and included sex, age, renal function, type of gadolinium administered, and subsequent cutaneous disorders. If a patient presented a cutaneous disorder, a skin biopsy was performed to confirm the diagnostic.Results The 308 eligible patients had a mean age of 59.9 years, 59% were men, and 54% had stage 5 RI. 75% of those 308 patients received a Gadolinium chelate. Among those patients who received a gadolinium chelate, 76% received gadoterate, 20% gadopentetate, 3% gadodiamide and 1% gadobenate. No cutaneous disorders were recorded after MRI. Conclusion These results confirm that NSF is a rare disease. Based on a reported frequency, ~3.5% in patients with glomerular filtration rate <30ml/min/1.73m2), some cases should have been observed in our study which included 308 patients. Most patients received gadoterate, a macrocyclic gadolinium chelate for which no case of NSF has been observed worldwide. This suggests that more stable macrocyclic agents may be less likely to induce NSF. Kadiyala D, Roer DA, Perazella MA. Nephrogenic systemic fibrosis associated with gadoversetamide exposure: treatment with sodium thiosulfate. Am J Kidney Dis 2009; 53(1):133-137. Abstract: Nephrogenic systemic fibrosis (NSF) is a debilitating fibrosing disorder of patients with kidney disease that is associated with gadolinium-based contrast exposure. Most cases are linked to gadodiamide. Gadoversetamide, an agent with chelate characteristics similar to gadodiamide, has rarely been described to cause NSF. With the exception of normalization of kidney function, there are no consistently effective therapies for patients with NSF. We describe 3 cases of NSF in patients with end-stage renal disease after gadolinium-based
A-9
contrast exposure. Two patients received gadoversetamide and the third received gadodiamide. All 3 patients were treated early in their disease course with intravenous sodium thiosulfate and responded with improved skin changes and joint mobility.
Kallen AJ, Jhung MA, Cheng S, Hess T, Turabelidze G, Abramova L et al. Gadoliniumcontaining magnetic resonance imaging contrast and nephrogenic systemic fibrosis: a casecontrol study. Am J Kidney Dis 2008; 51(6):966-975. BACKGROUND: Nephrogenic systemic fibrosis (NSF) is a newly described disorder occurring in persons with renal failure. Gadolinium-based contrast used in magnetic resonance imaging (MRI) has been suggested as a cause. A cluster of patients with NSF was investigated to identify risk factors. Limited preliminary findings from this investigation were presented in the Morbidity and Mortality Weekly Report. STUDY DESIGN: Matched case-control. SETTING & PARTICIPANTS: Dialysis patients with and without a diagnosis of NSF treated at an academic medical center. PREDICTOR: Exposure to gadolinium-based contrast. OUTCOMES & MEASUREMENTS: Laboratory and clinical characteristics of NSF. RESULTS: 19 of 28 cases identified at the hospital from December 2002 to August 2006 met inclusion criteria and were matched to 57 controls. In univariate analysis, receipt of gadolinium-containing MRI contrast in the preceding year (odds ratio [OR], 7.99; 95% confidence interval, 2.22 to 28.8) was associated with NSF; the measure of association increased as cumulative dose increased. Gadodiamide exposure (OR, 9.83; 95% confidence interval, 2.09 to 46.2) was associated more strongly with NSF than gadoversetamide (OR, 1.82; 95% confidence interval, 0.33 to 10.2). Although not statistically significant, cases were more likely than controls to have undergone primarily peritoneal dialysis in the preceding 6 months. There was no significant difference in receipt of high-dose recombinant erythropoietin between cases and controls. In multivariable analysis, gadolinium contrast exposure (OR, 8.97; 95% confidence interval, 1.28 to 63.0) remained significantly associated with NSF. LIMITATIONS: Retrospective design, small sample size, inability to completely evaluate erythropoietin. CONCLUSIONS: Receipt of gadolinium-containing MRI contrast is associated with NSF in a dose-dependent manner. The risk associated with gadolinium may differ by contrast agent and dialysis modality. Use of gadolinium-based contrast agents should be avoided when possible in patients with renal failure
Lauenstein TC, Salman K, Morreira R, Tata S, Tudorascu D, Baramidze G et al. Nephrogenic systemic fibrosis: Center case review. J Magn Reson Imaging 2007; 26(5):1198-1203.
A-10
PURPOSE: To retrospectively analyze nephrogenic systemic fibrosis (NSF) cases at our center, to determine prior gadolinium based contrast agent (GBCA) administration and to evaluate possible common risk factors for the development of NSF by reviewing laboratory data and concurrent medications. MATERIALS AND METHODS: A total of four data bases (pathology, MRI, dialysis, and medical records) were cross-referenced for identification and evaluation of NSF patients. Medical history of NSF patients was assessed as for previous deep venous thrombosis (DVT), surgery, or infections. Laboratory data (creatinine, anion gap, calcium, phosphorus, and albumin) as well as concurrent medication were evaluated. Findings were compared to those of a control group of non-NSF dialysis patients. RESULTS: Between October 2003 and February 2007 a total of nine NSF cases were identified. All patients had undergone contrast-enhanced MRI prior to the diagnosis of NSF. Only one gadolinium chelate had been used at our MRI center (Omniscan(R), gadodiamide; GE Healthcare). Of nine patients, eight were receiving dialysis at the time of the MRI scan. During the same time 312 dialysis patients received gadodiamide. Thus, the prevalence of NSF within dialysis patients exposed to gadodiamide was 2.6%. NSF patients presented with a higher creatinine and anion gap than the control patients. Other laboratory values as well as medication did not show a significant difference. There were no patterns regarding previous history of DVT, surgery, or infection in the NSF group. CONCLUSION: Our findings are consistent with the previously reported association between gadodiamide exposure and NSF. All NSF patients had severe renal insufficiency with glomerular filtration rate (GFR) < 30 (highest GFR = 25 mL/minute) at the time of last gadodiamide administration, and on average had received 71 mL of gadodiamide over an average of 2.9 administrations. J. Magn. Reson. Imaging 2007;26:1198-1203. (c) 2007 WileyLiss, Inc.
Levey AS, Coresh J, Balk E, Kausz AT, Levin A, Steffes MW et al. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Ann Intern Med 2003; 139(2):137-147. Abstract: Chronic kidney disease is a worldwide public health problem with an increasing incidence and prevalence, poor outcomes, and high cost. Outcomes of chronic kidney disease include not only kidney failure but also complications of decreased kidney function and cardiovascular disease. Current evidence suggests that some of these adverse outcomes can be prevented or delayed by early detection and treatment. Unfortunately, chronic kidney disease is underdiagnosed and undertreated, in part as a result of lack of agreement on a definition and classification of its stages of progression. Recent clinical practice guidelines by the National Kidney Foundation 1) define chronic kidney disease and classify its stages, regardless of underlying cause, 2) evaluate laboratory measurements for the clinical assessment of kidney disease, 3) associate the level of kidney function with complications of chronic kidney disease, and 4) stratify the risk for loss of kidney function and development of cardiovascular disease. The guidelines were developed by using an approach based on the procedure outlined by the
A-11
Agency for Healthcare Research and Quality. This paper presents the definition and five-stage classification system of chronic kidney disease and summarizes the major recommendations on early detection in adults. Recommendations include identifying persons at increased risk (those with diabetes, those with hypertension, those with a family history of chronic kidney disease, those older than 60 years of age, or those with U.S. racial or ethnic minority status), detecting kidney damage by measuring the albumin-creatinine ratio in untimed ("spot") urine specimens, and estimating the glomerular filtration rate from serum creatinine measurements by using prediction equations. Because of the high prevalence of early stages of chronic kidney disease in the general population (approximately 11% of adults), this information is particularly important for general internists and specialists.
Marckmann P, Skov L, Rossen K, Dupont A, Damholt MB, Heaf JG et al. Nephrogenic Systemic Fibrosis: Suspected Causative Role of Gadodiamide Used for Contrast-Enhanced Magnetic Resonance Imaging. J Am Soc Nephrol 2006; 17:2359-2362. Abstract: Nephrogenic systemic fibrosis is a new, rare disease of unknown cause that affects patients with renal failure. Single cases led to the suspicion of a causative role of gadodiamide that is used for magnetic resonance imaging. This study therefore reviewed all of the authors' confirmed cases of nephrogenic systemic fibrosis (n = 13) with respect to clinical characteristics, gadodiamide exposure, and subsequent clinical course. It was found that all had been exposed to gadodiamide before the development of nephrogenic systemic fibrosis. The delay from exposure to first sign of the disease was 2 to 75 d (median 25 d). Odds ratio for acquiring the disease when gadodiamide exposed was 32.5 (95% CI 1.9 to 549.2; P < 0.0001). Seven (54%) patients became severely disabled, and one died 21 mo after exposure. No other exposure/event than gadodiamide that was common to more than a minority of the patients could be identified. These findings indicate that gadodiamide plays a causative role in nephrogenic systemic fibrosis.
Mistry S, Ives N, Harding J, Fitzpatrick-Ellis K, Lipkin G, Kalra PA et al. Angioplasty and STent for Renal Artery Lesions (ASTRAL trial): rationale, methods and results so far. J Hum Hypertens 2007; 21(7):511-515. Abstract: Atherosclerotic renovascular disease (ARVD) is a relatively common condition which may lead to progressive renal dysfunction, and eventually to end-stage renal failure. Revascularization has been used in an attempt to prevent progression of ARVD, despite a lack of evidence for a benefit on kidney function. Therefore, large-scale randomized trials are needed to determine reliably whether or not there is any worthwhile benefit. The Angioplasty and STent for Renal Artery Lesions (ASTRAL) trial comparing renal function in ARVD patients randomized to either revascularization or medical management alone was designed to provide this evidence. ASTRAL started recruiting in November 2000 and, as of the end of 2006, 731 patients have been randomized into the trial (19 patients short of its minimum target of 750 patients). A pooled analysis (not split by treatment arm) of all patients shows that serum creatinine increased in the first 6 months then remained relatively steady, whereas blood
A-12
pressure has decreased from baseline. The trial is due to close to recruitment in April 2007, with the first presentation of the results of the randomized treatment comparison planned for the spring of 2008. To date ASTRAL is by far the largest randomized trial in ARVD, and will provide the most reliable and timely evidence on the role, if any, of revascularization in ARVD with which to guide the treatment of future patients. Morris MF, MacGregor J, Zhang H, Grossman M, Silvers D, Valeri A, Silberzweig J, Kapoor R, McNutt N and Prince MR. Factors relating to development of Nephrogenic Systemic Fibrosis following Gadolinium. Proc. Intl. Soc. Mag. Reson. Med. 15 (2007) 739 Abstract: A retrospective case-control study of gadolinium-enhanced magnetic resonance imaging and nephrogenic systemic fibrosis in patients with renal failure. 07 Mar 9; 2007. Purpose: Two case series have implicated gadolinium contrast in Nephrogenic Systemic Fibrosis (NSF). We present the first case-control series of NSF, comparing the frequency and degree of exposure to gadolinium contrast agents amongst our renal failure population. Methods and Materials: Retrospective analysis of all dialysis patients between 1st January 2000 and 1st July 2006. Diagnoses of NSF, episodes of gadolinium-enhanced MRI and cumulative gadolinium doses. Outcomes analysed by parametric and non-parametric testing. Results: Of 1826 patients on dialysis, 425 (23.3%) underwent 583 gadolinium-enhanced MRI studies. For 522 (89.5%) gadodiamide (median dose volume 30 ml) was used, others received gadobenate dimeglumine, gadopentetate DTPA, gadofosveset trisodium or gadobutrol. 12/1826 patients had confirmed NSF, 11 of these had received gadolinium contrast compared with 414/1814 non-NSF patients (p<0.001). They had received a higher cumulative dose of gadolinium (p<0.001) and demonstrated a trend towards more gadolinium-enhanced MRI (p=0.082). However, while median time to onset of NSF was 53 days; in one patient this was 487 days, in 2 it was > 200 days and in one symptoms started before contrast administration. All patients exposed to gadolinium contrast who developed NSF had received gadodiamide though this was the dominant contrast agent used. Conclusion: A strong association between administration of gadolinium contrast (gadodiamide) and NSF exists; however, the case without exposure and the onset time intervals in others suggest this is not the only cause. We recommend that at present gadolinium contrast be used with caution in patients with stage 5 kidney disease.
Newhouse JH, Kho D, Rao QA, Starren J. Frequency of serum creatinine changes in the absence of iodinated contrast material: implications for studies of contrast nephrotoxicity. AJR Am J Roentgenol 2008; 191(2):376-382. OBJECTIVE: Most studies of contrast-induced nephropathy lack controls to distinguish it from nephropathy from other causes. We assessed the frequency and magnitude of serum creatinine changes in patients not receiving iodinated contrast material to compare with creatinine changes in publications regarding contrast nephropathy.
A-13
MATERIALS AND METHODS: From the electronic medical records of an academic medical center, adults with creatinine determinations on five consecutive days who had not received contrast material during the previous 10 days were identified. The first creatinine level was compared with those on subsequent days. We calculated the frequency with which these levels exceeded thresholds used to identify contrast nephropathy in previous publications. RESULTS: Among 32,161 patients, more than half showed a change of at least 25% and more than two fifths, a change of at least 0.4 mg/dL. Among patients with baseline creatinine levels of 0.6-1.2 mg/dL, increases of at least 25%, 33%, and 50% occurred in 27%, 19%, and 11% of patients, respectively. Increases of 0.4, 0.6, and 1.0 mg/dL occurred in 13%, 7%, and 3% of patients. Among patients with baseline creatinine levels greater than 2.0 mg/dL, increases of at least 25%, 33%, and 50% occurred in 16%, 12%, and 7%. Increases of 0.4, 0.6, and 1.0 mg/dL occurred in 33%, 26%, and 18%. These increases were not different from the incidences of contrast nephropathy previously published. CONCLUSION: The creatinine level increases in patients who are not receiving contrast material as often as it does in published series of patients who are receiving contrast material. The role of contrast material in nephropathy may have been overestimated.
Othersen JB, Maize JC, Woolson RF, Budisavljevic MN. Nephrogenic systemic fibrosis after exposure to gadolinium in patients with renal failure. Nephrol Dial Transplant 2007; 22(11):3179-3185. BACKGROUND: Nephrogenic systemic fibrosis is a debilitating disease occurring exclusively in patients with renal failure. The aetiology of nephrogenic systemic fibrosis is unclear, but recent reports suggest that exposure to gadolinium for enhancement of magnetic resonance imaging may play a role. In the present study, we assessed the association of exposure to gadolinium with the development of nephrogenic systemic fibrosis in patients with various stages of chronic kidney disease. METHODS: We analysed the exposure to gadolinium and development of nephrogenic systemic fibrosis in 849 patients on renal replacement therapy over 5 years. We also performed inquiry of development of the nephrogenic systemic fibrosis in 592 patients exposed to gadolinium and estimated to be in stages 3 and 4 of chronic kidney disease. RESULTS: In 849 patients undergoing chronic dialysis from 2001 through 2006 time period, four of the 261 who had received gadolinium (1.5%) and none of the 588 not exposed to gadolinium developed clinically apparent disease. The odds ratio for developing nephrogenic systemic fibrosis was 6.671 [95% CI 1.537-53.97] in patients with a single gadolinium exposure compared to patients without gadolinium exposure. This ratio increased to 44.5 (95% CI 2.362-2913) in patients with multiple gadolinium exposures compared to patients not receiving gadolinium. None of the 592 patients estimated to be in stage 3 or 4 of chronic kidney disease developed nephrogenic systemic fibrosis after exposure to gadolinium.
A-14
CONCLUSION: Gadolinium exposure is associated with nephrogenic systemic fibrosis in patients on chronic renal replacement therapy at a low rate. This association appears to increase with repeated exposure to gadolinium. Since nephrogenic systemic fibrosis may be clinically occult, its prevalence may be higher than reported. Despite this association, it is unclear if gadolinium is the sole or most important factor in the pathogenesis of the disease.
Prince MR, Zhang H, Morris M, MacGregor JL, Grossman ME, Silberzweig J et al. Incidence of nephrogenic systemic fibrosis at two large medical centers. Radiology 2008; 248(3):807816. PURPOSE: To determine the incidence and associated risk factors of nephrogenic systemic fibrosis (NSF) in patients who undergo gadolinium-based contrast agent (GBCA)-enhanced magnetic resonance (MR) imaging. MATERIALS AND METHODS: Institutional review board approval was obtained for retrospective review of the medical records from two hospitals to identify all cases of biopsyconfirmed NSF and all patients administered a GBCA from January 1, 1997, to June 30, 2007. Informed patient consent was not required. The incidence of NSF was calculated for patients who received a standard dose of GBCA, patients who received a high dose, and subgroups of patients with renal impairment. RESULTS: Fifteen patients developed NSF after gadolinium-enhanced MR imaging. All of them had an estimated glomerular filtration rate (eGFR) lower than 30 mL/min, and 11 had acute renal failure or acute deterioration of chronic renal failure. The incidence of NSF after gadolinium-enhanced MR imaging without screening for renal function was zero of 74,124 patients with the standard dose of GBCA and 15 (0.17%) of 8997 patients with the high dose (P < .001). The NSF incidence associated with a high dose of GBCA increased to 0.4% in patients in a chronic hemodialysis program and to 8.8% in those who had an eGFR lower than 15 mL/min but were not undergoing hemodialysis (P < .001). The NSF incidence in the patients with acute renal failure who received a high dose when their creatinine level was increasing was 19% (11 of 58 patients) when hemodialysis was delayed for longer than 2 days. More patients with NSF had proinflammatory events, and compared with patients without NSF, these patients had lower pH, younger age, lower eGFR, elevated serum phosphorus levels, and a longer delay between GBCA injection and hemodialysis. CONCLUSION: For patients with an eGFR lower than 15 mL/min, hemodialysis helped to prevent NSF. For patients with an eGFR lower than 30 mL/min who received a high dose of GBCA, acute renal failure, delayed hemodialysis after contrast agent injection, proinflammatory events, and hyperphosphatemia were associated with increased risk of NSF.
Reilly RF. Risk for nephrogenic systemic fibrosis with gadoteridol (ProHance) in patients who are on long-term hemodialysis. Clin J Am Soc Nephrol 2008; 3(3):747-751.
A-15
Abstract: BACKGROUND AND OBJECTIVES: Recent studies strongly link nephrogenic systemic fibrosis to gadolinium administration for magnetic resonance imaging. In a recent advisory, the Food and Drug Administration stated that all gadolinium-containing chelates are potentially associated with nephrogenic systemic fibrosis; however, most reported cases are linked to gadodiamide (Omniscan) and gadopentetate dimeglumine (Magnevist). Given the severe consequences of nephrogenic systemic fibrosis, it is critical to define the risks associated with each gadolinium-containing chelate. The purpose of this study was to examine nephrogenic systemic fibrosis risk in a hemodialysis population exposed to gadoteridol (ProHance). DESIGN, SETTING, PARTICIPANTS, & OBJECTIVES: Appointment logs were used to generate a database of all long-term hemodialysis patients at the Dallas Veterans Affairs hospital since August 2001. These patients were then examined in the Veterans Affair's electronic medical record system for gadolinium exposure during magnetic resonance imaging from 2000 through 2007, a period during which gadoteridol was the sole contrast agent used. RESULTS: A total of 141 patients were identified with 198 gadoteridol exposures. No cases of nephrogenic systemic fibrosis were identified. The observed frequency of nephrogenic systemic fibrosis was compared with the expected frequency (2.4%) using one-way chi(2) and binomial analysis, yielding a P < 0.05, indicating that the result was not explained by chance alone. CONCLUSIONS: It is concluded that the risk for nephrogenic systemic fibrosis with gadoteridol in patients who are on long-term hemodialysis may be lower than with gadodiamide and gadopentetate dimeglumine.
Rydahl C, Thomsen HS, Marckmann P. High Prevalence of Nephrogenic Systemic Fibrosis in Chronic Renal Failure Patients Exposed to Gadodiamide, a Gadolinium-Containing Magnetic Resonance Contrast Agent. Invest Radiol 2008; 43(2):141-144. OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a serious disease affecting renal failure patients. It may be caused by some gadolinium (Gd)-containing contrast agents, including gadodiamide. The study aimed at estimating the prevalence of NSF after gadodiamide exposure for patients with chronic kidney disease (CKD). MATERIALS AND METHODS:: Retrospective cohort study of 190 consecutive nephrological patients in different categories of kidney function referred for gadodiamideenhanced magnetic resonance imaging in the period January 1, 2004 to March 21, 2006. RESULTS: Eighteen patients (18/190; 10%, 95% CI: 6%-15%) were diagnosed with NSF within a mean follow-up period of 29 months (range 16-43 months). All 18 cases had stage 5 CKD (ie, estimated glomerular filtration rate less than 15 mL/min/1.73 m or in dialysis therapy) at the time of their gadodiamide exposure. The prevalence of NSF among patients with stage 5 CKD at exposure (n = 102) was 18% (95% CI: 11%-27%). No cases were seen
A-16
among 88 gadodiamide-exposed patients who had milder degrees of renal insufficiency (prevalence 0%, 95% CI: 0%-4%). CONCLUSIONS: The risk of NSF is unacceptably high among stage 5 CKD patients exposed to gadodiamide.
Sadowski EA, Bennett LK, Chan MR, Wentland AL, Garrett AL, Garrett RW et al. Nephrogenic Systemic Fibrosis: Risk Factors and Incidence Estimation. Radiology 2007; 243(1):148-157. Purpose: To retrospectively review data in 13 patients with biopsy-confirmed nephrogenic systemic fibrosis (NSF), assess the associated risk factors, and report the incidence of NSF at the authors' institution. Materials and Methods: This HIPAA-compliant study had institutional review board approval; informed consent was waived. Statistical analysis was performed for all available clinical and laboratory data in patients with biopsy-confirmed NSF. The data from the patients with NSF were compared with data from a control population of patients with renal insufficiency but who did not develop NSF. Results: There were eight male and five female patients, aged 17-69 years, with a diagnosis of NSF. Within 6 months of diagnosis, all 13 patients had been exposed to gadodiamide and one had been exposed to gadobenate dimeglumine in addition to gadodiamide. At the time of contrast material-enhanced magnetic resonance (MR) imaging, all 13 patients had renal insufficiency (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) and were hospitalized for a proinflammatory event (major surgery, infection, or vascular event). The group with NSF had significantly decreased eGFR (P = .01), more proinflammatory events (P < .001), and more contrast-enhanced MR examinations per patient (P = .002) than did the control group. Conclusion: A combination of factors, including altered kidney function, inflammatory burden, and exposure to gadolinium-based contrast agents may all play a role in development of NSF. Alternative imaging should be considered in patients with these factors. If use of a gadoliniumbased agent is clinically indicated, the referring physician and patient should be informed of the potential risk of developing NSF. (C) RSNA, 2007 Salman KN, Moreira R, Sharma P, Tudorascu D, Holder C, Martin DR. Evaluation of a Possible Risk Association between Nephrogenic Sclerosing Dermopathy (NFD) and Gadolinium Enhanced MRI. Proc Intl Soc Magn Res Med 2007; 15:742.
Todd DJ, Kagan A, Chibnik LB, Kay J. Cutaneous changes of nephrogenic systemic fibrosis: Predictor of early mortality and association with gadolinium exposure. Arthritis Rheum 2007; 56(10):3433-3441.
A-17
OBJECTIVE: Nephrogenic systemic fibrosis (NSF) is a rapidly progressive, debilitating condition that causes cutaneous and visceral fibrosis in patients with renal failure. Little is known about its prevalence or etiology. The aim of this study was to establish the prevalence of NSF and associated risk factors METHODS: Two cohorts of patients were recruited from 6 outpatient hemodialysis centers and examined for cutaneous changes of NSF, which were defined using a scoring system based on hyperpigmentation, hardening, and tethering of skin on the extremities. Demographic data were gathered, mortality was followed up prospectively for 24 months, and gadolinium exposure was ascertained for a subgroup of patients in the second cohort. RESULTS: Examination reproducibility was 97% in cohort 1. In cohort 2, 25 (13%) of 186 patients demonstrated cutaneous changes of NSF. Twenty-four-month mortality following examination was 48% and 20% in patients with and those without cutaneous changes of NSF, respectively (adjusted hazard ratio 2.9, 95% confidence interval [95% CI] 1.4-5.9). Cutaneous changes of NSF were observed in 16 (30%) of 54 patients with prior exposure to gadopentetate dimeglumine contrast during imaging studies. Exposure to gadolinium-containing contrast was associated with an increased risk of developing cutaneous changes of NSF (odds ratio 14.7, 95% CI 1.9-117.0) compared with nonexposed patients. CONCLUSION: In patients receiving hemodialysis, NSF is an underrecognized disorder that is associated with increased mortality. Exposure to gadolinium-containing contrast material appears to be a significant risk factor for the development of NSF.
Wahba IM, Simpson EL, White K. Gadolinium is not the only trigger for nephrogenic systemic fibrosis: insights from two cases and review of the recent literature. Am J Transplant 2007; 7(10):2425-2432. Abstract: Nephrogenic systemic fibrosis (NSF) is an emerging fibrosing disease with serious consequences in patients with acute and chronic kidney disease including solid organ and renal transplant recipients. It has recently been linked to gadolinium exposure. Almost all recently reported cases of NSF were found to be preceded by gadolinium administration, which led the FDA to issue a warning against the use of gadolinium in patients with moderate-to-severe reduction in the glomerular filtration rate. We report two organ transplant recipients who developed NSF and in whom extensive record review failed to document any prior gadolinium exposure. We then critically review the recently published literature linking NSF and gadolinium and we propose other possible triggers. We conclude that gadolinium is not the only trigger for NSF, and that the search for other triggers should be sought. We believe that this information is an important addition to the NSF literature, such that the definitive etiology and pathogenesis of NSF can be researched.
A-18
Wertman R, Altun E, Martin DR, Mitchell DG, Leyendecker JR, O'Malley RB et al. Risk of nephrogenic systemic fibrosis: evaluation of gadolinium chelate contrast agents at four American universities. Radiology 2008; 248(3):799-806. PURPOSE: To retrospectively determine the benchmark incidence of nephrogenic systemic fibrosis (NSF) related to the confirmed use of different gadolinium chelate contrast agents at four U.S. university tertiary care centers. MATERIALS AND METHODS: Institutional review board approval was obtained for this HIPAA-compliant multi-institutional study; the requirement for informed patient consent was waived. Patients who had a diagnosis of NSF between January 2000 and December 2006 were identified at four tertiary care centers with renal transplant and dialysis services. A standard checklist was used to acquire reliable data from the four centers. The diagnosis of NSF was confirmed histopathologically in all patients. The association of NSF development with gadolinium chelate contrast agent administration in each patient was assessed. The type and cumulative dose of contrast agent administered to each patient with NSF were determined at each center by using the standard checklist. The benchmark incidence of NSF was determined and expressed as the ratio of the number of patients with NSF who had undergone gadolinium chelate-enhanced magnetic resonance (MR) imaging, relative to the total number of patients who underwent gadolinium chelate-enhanced MR imaging at each tertiary care center. Benchmark incidences of NSF were compared among the four centers by using Fisher exact tests. RESULTS: Gadodiamide was used at University of North Carolina at Chapel Hill (center A) and Emory University (center B), and gadopentetate dimeglumine was used at Wake Forest University (center C) and Thomas Jefferson University (center D) during the study period. Twenty-three patients at center A, nine patients at center B, three patients at center C, and one patient at center D had NSF and had undergone gadolinium chelate-enhanced MR imaging. The incidence of NSF was one in 2913 patients who underwent gadodiamide-enhanced MR examinations and one in 44,224 patients who underwent gadopentetate dimeglumine-enhanced MR examinations. CONCLUSION: The benchmark incidence of NSF was much greater at the two centers where gadodiamide was used than at the two centers where gadopentetate dimeglumine was used. Wollanka H, Weidenmaier W, Giersig C. NSF after Gadovist exposure: a case report and hypothesis of NSF development. Nephrol Dial Transplant 2009. Abstract: So far no cases of nephrogenic systemic fibrosis (NSF) have been published on macrocyclical gadolinium-based contrast media (Gd-CM), assumed as low NSF risk CM due to their complex stability. In our haemodialysis-dependent patient, the first symptoms indicating NSF appeared about 16 months after the exposure to Gadovist, a macrocyclical GdCM, and 1 month after x-ray angiography with iodinated CM (Ultravist). This indicates that in addition to excretory renal failure and Gd-CM exposure, the loss of biosynthetic renal function could be essential for NSF development. A hypothesis of possible pathways involved in the development of NSF is presented.
A-19
APPENDIX B
Nonclinical Studies
Summary of Mechanism Studies (in vitro studies) GEHC collaborative studies have shown that chelated-Gd3+ (gadodiamide and gadopentetate), might directly stimulate human monocytes and macrophages to release profibrotic cytokines and growth factors that are capable of initiating and supporting the tissue fibrosis that is characteristic of NSF (Wermuth 2008 and 2009). In these studies human peripheral blood monocytes were exposed to varying concentrations of GBCAs and GdCl3. Changes in expression levels of relevant cytokines and growth factors were assessed by real-time polymerase chain reaction (rt PCR) of RNA isolated from peripheral blood monocytes and by quantitative assessment of numerous cytokines, growth factors, and other inflammatory mediators employing Searchlight ELISA of culture media. Cytokine (IL-6, IL-13, TGF- and VEGF) levels assayed in culture supernatants from the treated cells by Searchlight ELISA confirmed the increased secretion of profibrotic cytokines and growth factors to chelated-Gd3+. Such studies provide a direct mechanistic link with the histopathological findings of Thakral and Abraham (Thakral and Abraham 2007), High et al (High 2007) and Jimenez et al (Jimenez 2004). In a series of follow-up studies, Del Galdo et al (Del Galdo 2008) exposed terminally differentiated human peripheral blood macrophages to either gadodiamide or saline before isolating and analysing cellular RNA for global gene expression microarray analysis. Volcano plot analysis of the microarray data revealed that 31 genes were up-regulated by more than two-fold in the gadodiamide treated macrophages (p<0.05). Pathway analysis and rt PCR validation of the up-regulated genes strongly suggested the participation of Toll-Like Receptor (TLR) mediated activation and immunofluorescence analysis of activated cells demonstrated NFB translocation from the cytosol to the nucleus. Indeed 5 out of 9 genes were chemokine genes from the CC and the CXC families. ELISA of culture supernatants from cultured macrophages exposed to gadodiamide indicated that CCL2, CCL8, CXCL10 and CXCL11 were up-regulated between 10 and 240 fold higher than saline controls. Correspondingly, immunofluorescence analysis of NSF skin biopsies revealed that CCL8 (MCP-2) was preferentially up-regulated compared to normal skin. Such observations support the mechanistic relevance of the in vitro studies. Similarly, a direct effect of chelated-Gd3+ has also been demonstrated on fibroblasts in vitro. In a study by Edward et al (2008), gadodiamide added to culture medium, stimulated fibroblast growth. In the same study, fibroblasts expressed and synthesized increased levels of hyaluronan. NSF Fibroblasts cultured from the lesions of six NSF patients, all of whom were exposed to gadodiamide, synthesized excess levels of hyaluronan and collagen compared to control fibroblasts. In a separate study by Varani (Varani 2009), GdCl3 and chelated-Gd3+ (gadodiamide, gadopentetate, gadobenate, and gadoteridol) all increased proliferation of human dermal
A-20
fibroblasts in monolayer culture. Interestingly, GdCl3 was also shown to stimulate the proliferation of fibroblasts to a small extent; there were clear differences between the GdCl3 and GBCA responses. The magnitude of proliferation was lower than chelated gadolinium, there was a sharp fall-off in cell number with M concentrations of GdCl3, and the fall-off in cell number was associated with cytotoxicity and detectable precipitate formation in the cell culture medium. The fall-off in cell number and cytotoxicity were not observed with the GBCAs at similar (M) concentrations. Additionally, increased proliferation of cells associated with GBCA was accompanied by an increase in production of Matrix Metalloproteinase-1 (MMP-1) and Tissue Inhibitor of Matrix Metalloproteinase-1 (TIMP-1) but no increase in type I procollagen in whole skin organ in culture (Varani 2009). Once again such studies provide a direct mechanistic link with the histopathological findings of Jimenez (Jimenez 2004). Perhaps more importantly, NSF patient serum stimulated control skin fibroblasts in vitro while healthy control serum was without effect. This indicates that substances other than GBCAs, e.g. proinflammatory and or profibrotic cytokines, are secreted into serum by monocytes and or macrophages after GBCA exposure, and could control or participate in the pathogenesis of NSF. Similarly, Wermuth (Wermuth 2008) has demonstrated that conditioned media isolated from GBCA-exposed PBMC caused cultured human dermal fibroblasts to increase expression of extracellular matrix proteins and -SMA indicating their conversion into myofibroblasts. Since these studies show that it is possible for products of inflammatory cells to induce a fibrotic phenotype in normal dermal human fibroblasts in vitro, it is not inconceivable that GBCA could stimulate inflammatory cells to secrete the mediators essential to the development of NSF in vivo. It should be noted that all but one of the six samples studied in the Edward experiments came from NSF patients with a pre-existing inflammatory condition at the time of their enhanced scans (Edward 2008).
A-21
APPENDIX C
Animal Modes (in vivo studies)
Although recent publications by Sieber claim to have developed an NSF-like model, rats in that study had normal renal function and the key features of NSF skin pathology were not present in those rats with reported skin changes (Sieber 2008a). The paper described skin lesions in rats treated for 20 days with either formulated (Omniscan) or unformulated gadodiamide. The study reported only minimal to slight dermal fibrosis and increased infiltration of different cells, partly positive for CD34+ cells. The authors concluded that gadodiamide dosing resulted in the formation of NSF-like skin lesions. Gadoversetamide, gadopentetate, gadobenate and gadoterate did not cause NSF-like skin lesions in this model. Sieber concluded that the amount of Gd in skin was related to the in vitro stability of GBCAs since skin lesions had only superficial fibrosis, which appeared to correlate with amount of gadolinium in the skin. However this conclusion must be questioned because the level of gadolinium was assessed by inductively coupled plasma atomic emission spectrometry (ICPAES), which is not able to differentiate the form of gadolinium or if it was still contained within the chelate. The lesions were similar, at the macroscopic and histopathologic level, to those reported 16 years ago in a repeat dose study by Harpur et al (Harpur 1993). The Harpur study also described superficially thickened skin and scab formation after 5mmol/kg Omniscan repeatedly dosed over 20 days. The Harpur paper reported rat studies conducted by Hazleton Laboratories America (HLA), Inc. between May and June 1988 (HLA study number 2493112), and was part of a program to evaluate the preclinical safety of Omniscan (gadodiamide) as part of the clinical development studies (Sponsor was Salutar Inc. (Sunnyvale, California)). In order to both investigate the claims made by Sieber (Sieber 2008a) and if the rat skin lesions reported in the Harpur study resembled human NSF, GE Healthcare carried out an independent peer review of study 2493-112 and additional studies to further investigate the effect of GBCA in the rat. The peer review panel of pathologists unanimously concluded that NSF-like skin lesions were not present in any rats treated with Omniscan. Lesions of the skin were present in males administered with high dose only; the characteristic finding was an ulcerative lesion of the epidermis with inflammation extending into the subepidermal regions. Skin adnexal structures showed folliculitis or dermal cellulites corresponding to the extent of the lesions. Although the cause of these cutaneous lesions was not established in the peer review, such lesions in rodents are commonly associated with trauma to the skin, likely initiated by pruritus. A new internal study has recently been reported (Grant 2009). Nave or partially nephrectomised rats administered intravenous doses of gadopentetate, gadodiamide, formulated gadodiamide, caldiamide (i.e. the calcium-containing chelate in Omniscan), GdCl3 or Gd citrate. Similar responses to treatment were seen in nave and nephrectomised rats over the 18 day study period. High doses of gadodiamide were toxic, necessitating early termination of the affected animals. Skin lesions appeared in nave and nephrectomised rats treated with formulated or unformulated gadodiamide, coinciding with the onset of signs of pruritus, i.e., intensive scratching. The histomorphological features of the skin lesions were also consistent with superficial physical trauma. Dermal fibrosis was not a feature of these skin lesions in any of the groups, i.e., no increased collagen density, CD34+ cells, or increased
A-22
fibroblasts. The visible skin lesions seen in this study appeared to be caused by excessive scratching in response to pruritus. As there was no evidence of dermal fibrosis, the cardinal feature of human NSF, this did not appear to be a model of human NSF (Grant 2009). Since the above studies were of short term (several weeks) duration, GE Healthcare also carried out an external collaborative rat study to investigate the longer term effects of GBCA exposure in rat. In these studies three groups of 10 Sprague Dawley rats having surgical resections of approximately 83% of their total renal masses received 0.3 mmol Gd/kg (equivalent to 3 times the human dose), intravenously on each of three consecutive days of gadodiamide, gadopentetate or gadoteridol respectively. Animals were observed for development of skin lesions over 90 days. Pathologic examination of skin, diaphragm, liver, lung, heart, and mesentery were performed either at the end of the 90-day period or when any single skin lesion exceeded 1 cm in diameter. Results demonstrated that blood urea nitrogen was elevated >300% of normal in all partially nephrectomised rats. One or more erythematous skin lesions were observed in 7, 5, and 6 animals respectively from each group of 10 receiving gadodiamide, gadopentetate or gadoteridol with skin lesions generally first appearing between 14 and 21 days after 9-fold standard dosing and often disappearing spontaneously in 3 to 5 days more. Groups were not statistically different. Pathology revealed no deep dermal or internal organ fibrotic lesions characteristic of human NSF. It was concluded that NSF was not induced in these rats challenged with the three most widely-used GBCAs administered maximum clinical doses even in rats with renal insufficiency. The view that NSF is the consequence of Gd-chelate dissociation in the setting of renal failure with prolonged, relatively-high exposure to GBCAs may be overly simplistic. These data were presented at the 2009 European Society of Radiology Meeting in Vienna. These skin data conflict with recently published data from Pietsch (Pietsch 2009). In Pietschs study, several GBCAs were injected on five consecutive days with a dose of 2.5 mmol/kg bodyweight into the tail vein of Han-Wistar rats and the Gd concentrations were determined by Inductively Coupled Plasma Mass Spectrometry (ICP-MS). The authors suggest a correlation between the complex stability of GBCAs and the amount of residual gadolinium in the skin up to a year after application of GBCAs, such as formulated gadodiamide. However, it is not clear if the retention leads to skin lesions or to the pathology that was observed in the Sieber paper above. Additionally the form of retained gadolinium i.e. whether chelated-Gd was retained, could not be investigated by ICP-MS. A further GE study is in progress to clarify this. Since only high dose gadodiamide exposure appears to result in intense lesion formation in the rat, there is a possibility that this species has a predilection for developing such lesions. Daily intravenous injections for 28 days with 1.25 mmol/kg/day formulated gadodiamide to non-human primates, a cumulative dose of 35 mmol/kg or 117 times the maximum clinical dose, only produced renal proximal tubule vacuolation and reduced blood levels of zinc and inorganic phosphorus; no gross or microscopic skin lesions were seen (Harpur, 1993). The pruritus, excessive scratching and, as a consequence, superficial abrasions of the skin may explain the lesions in rats. As fibrosis, extending from the dermis, subcutaneous tissue down to the muscle fascia is a cardinal feature of human NSF, the lack of clear evidence of it in the Sieber and Grant studies, the absence of histomorphological changes in the rats dosed with
A-23
gadopentetate, coupled with the primate results from Harpur, suggest that the rat does not represent an appropriate model of NSF. Unfortunately in vivo studies carried out thus far in the rat do not support the conclusion that this species provides a predictive animal model of human NSF. The results from GE Healthcares studies have demonstrated that there is a considerable difference between skin lesions to repeated high doses of Omniscan and clinical NSF. The results of rat studies suggest that due to species, GBCA specific toxicity and technical challenges, it may be impossible to set up a predictive in vivo model of NSF. In addition to these issues, non-published data recently generated by GE Healthcare have shown that particles of retained Gd are not crystalline, so it is unlikely that Gd is in the form of gadolinium phosphate as has previously been postulated (Sieber 2008a and b, Thakral 2007). The results of these new analytical studies are as follows: After administration of the gadolinium-based contrast agents Omniscan and Magnevist, as well as GdCl3, to normal laboratory rats, ICP-AES showed measurable gadolinium concentration in the liver, skin, kidney, and spleen of all animals, as well as in other organs. In most cases the SEM imaging showed that the gadolinium was present as individual particle or clumps that were of the order of 0.1 1 micron in size. TEM imaging showed that these particles or clumps seen in the SEM consisted of aggregates of smaller particles of the order of 5 to 10 nm in size. However it was difficult to associate the location of particles with any specific cell type or constituent in any organ. Phosphorus (P) was seen to be the primary element present in the particle clumps. However electron diffraction showed that the gadolinium-P particles were amorphous, not crystalline, in nature. The fact that the particles are not crystalline suggests that the particles are not gadolinium phosphate as has previously been thought. The amorphous nature suggests that the gadolinium is associated with organic material (e.g. protein, phospholipids or microparticles) brought about by extra or intracellular processing of the gadolinium-chelate. In separate studies the biodistribution of gadolinium and ligand was studied in rats injected intravenously with Omniscan spiked with trace amounts of 14C-labelled GdDTPA-BMA. Biodistribution of the 14C-labelled ligand in whole animals was visualized using QWBA, and quantified in individual tissue samples by analyzing for radioactivity using beta-counting. Biodistribution of gadolinium was measured by ICP-AES and ICP-SF-MS. The injected dose was rapidly excreted, with less than 1.0% remaining in the body at 24 hours. The radioactivity at later time points was mainly associated with kidney cortex, liver, lung, muscle and skin, with a similar rate of clearance for both ligand and gadolinium from these tissues. The ratio between 14C-labelled substance and gadolinium was not significantly different from that of the injected substance in most tissue samples up to 24 hours after injection. The data clearly show that chelate and gadolinium remain in the skin of animals intravenously treated with Omniscan spiked with trace amounts of 14C-labelled GdDTPA-BMA. In addition the data show that measurements of gadolinium concentration alone in tissue samples from animals injected with GBCAs cannot be used as a measure of gadolinium released from the ligand (dechelation) as others have done (Pietsch 2009, Sieber 2008a and b). The amorphous nature suggests that the gadolinium is associated with organic material brought about by extra or intracellular processing of the Gd-chelate. Since NSF has only been observed at very low frequencies in patients with severely impaired renal failure, end stage renal disease
A-24
and those in acute renal failure (Deo 2007, Kuo 2007, Perazella 2007, Prince 2008) in combination with several cofactors, it is possible that a definitive animal model of NSF may be impossible to establish.
A-25
APPENDIX D
Proposed alternative hypothesis for the mechanism of NSF
These observations suggest that other co-factors previously associated with NSF may not be required e.g. EPO, metabolic acidosis and thrombotic events. These observations also permit an alternative hypothesis (Newton 2009). 1. Protracted retention of GBCA in renal insufficiency (e.g. SIRF, ESRD and ARF) provides the conditions for enhanced exposure of tissues to GBCA. 2. GBCA interacting with cells may be internalized via receptor driven phagocytosis in macrophages and receptor-mediated endocytosis in fibroblastic cells. 3. GBCA may trigger inflammatory and fibrotic responses in the tissues of susceptible cells. Receptor-mediated endocytosis of chelated Gd3+ has been shown by Franano who observed acid dependent metabolism of conjugated, chelated Gd3+ typical of lysosomal degradation at very low pH (Franano 1995). Release of profibrotic cytokines may precede lysosomal uptake of GBCA. Formation of tissue retained insoluble Gd3+-species may be a footprint of a receptor mediated cell response (Figure 10 and Figure 11). Such a mechanism is consistent with the identification of Gd3+-species localized in areas of dermal inflammation rich in macrophages in NSF (Thakral and Abraham 2007; Jimenez, 2004) and the detection of insoluble Gd3+-species of <1m in diameter confined to areas of fibrosis in NSF tissue (High 2007).
A-26
Figure 10 Schematic for release of profibrotic preceding formation of tissue retained insoluble Gd3+
Clearly NSF does not take place in every patient, thus some form of patient susceptibility is likely. Nevertheless, the data summarized below help explain why co-factors such as single high GBCA dose, SIRF and ESRD, dependent edema and pre-existing inflammation might predispose patients receiving GBCAs to develop NSF:
1. The protracted half life of GBCA in ESRD and SIRF (Kuo 2007) leads to the increased exposure of interstitial tissue to GBCAs. 2. High single dose rather than repeated standard doses of GBCA carries the greatest risk in vivo (Collidge 2007, Prince 2008). Post dose plasma concentrations of GBCA are in accord with the concentrations of GBCA that can directly stimulate inflammatory cells and fibroblasts in vitro. 3. The link between NSF and inflammatory "conditions" in vivo (Sadowski 2007) accords with the observations that macrophages and monocytes can be directly stimulated by GBCAs in vitro.
A-27
Figure 11 Schematic of the proposed mechanism
A-28
APPENDIX E
Table of Nonclinical Trials
Study 1a
Study Description To investigate the effect of repeated, high dose GBCA on the development of skin lesions in rats with normal and impaired 5/6 renal function (enabled by 5/6 nephrectomy).
Questions Addressed To histopathologically assess skin lesions (ulceration, mineralization and eschar) identified by Harpur et al. 1993 (Investigative Radiology 28, S28-S43) and their relationship to NSF in both groups. Does repeated high dosing of GBCA result in NSF in the rat?
Publication Status Abstract published EMRF (May 08) Abstract Accepted to ECR (Vienna March 2009) Grant D, Johnsen H. Juelsrud A. Lovhaug. Effects of gadolinium Contrast Agents in Naive and Nephrectomized Rats: Relevance to Nephrogenic Systemic Fibrosis, Acta Radiologica, 50 (2): 156-169, 2009.
Study Completion Completed
GE Rat Study B041005
A-29
1b
To determine the form of Gadolinium retained in tissues from GE Rat Study B041005
To assess location, distribution and form of Gadolinium in skin lesions and normal skin by Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM), ICPAES and QWBA. Do skin lesions develop under conditions of low dose and renal impairment? Does repeated low dosing of GBCA result in NSF in the renally impaired rat? Do GBCA induce NSF-like skin lesions in the rat?
Abstract submitted to ECR (Vienna March 2010) Full paper covering QWBA, SEM and TEM in preparation.
Ongoing. Not Yet Published
2a
Investigate the effect of three doses of GBCAs (Omniscan, Magnevist, Prohance 0.3mmol/kg i.v.) to rats with impaired renal function (enabled by 5/6 nephrectomy).
Abstract presented to ECR (Vienna March 2009)
Completed
Study
Study Description
Questions Addressed What is relevance of in vitro kinetic stability constants in the development of skin lesions?
Publication Status
Study Completion
2b
Investigate the effect of three doses of Omniscan and Prohance at 2.5mmol/kg ( i.v.) to rats with impaired renal function (enabled by 5/6 nephrectomy).
Do skin lesions develop under conditions of higher dose (equivalent to Sieber 2008) and renal impairment? Does repeated dosing of linear and cyclic GBCA result in NSF in the renally impaired rat? What is relevance of in vitro kinetic stability constants in the development of skin lesions?
Paper in preparation.
In life completed. Gadolinium analysis in tissues in progress.
A-30
3a
Induction of expression of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents ELISA study Identification of the factors released from the above cells.
Could the presence of inflammatory cells, shown to be present in End Stage Renal Disease (ESRD), predispose to / increase the risk of NSF?
Wermuth PJ, Del Galdo F, Jimnez SA. Induction of expression of profibrotic/proinflammatory proteins in normal human peripheral blood mononuclear cells (PBMC). Role in Pathogenesis of GadoliniumAssociated Nephrogenic Systemic Fibrosis. Abstract FRI0259. EULAR 2008. Ann Rheum Dis. 67 (suppl II): 366, 2008. Del Galdo F, Wermuth P, Jimenez SA. Activation of Toll-like Receptor
Completed
Study
Study Description
Questions Addressed
Publication Status Pathways and Induction of Chemokine Production in Normal Human Macrophages by a Gadolinium Containing Contrast Agent: Trigger Event in the Pathogenesis of Nephrogenic Systemic Fibrosis? Abstract 1803. ACR Congress 2008. Arthritis Rheum. 58: S831, 2008. Abstract published at ECR (Vienna March 2009) Wermuth PJ, Del Galdo F, Jimenez, SA. 2009. Induction of Expression of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents. Arthritis Rheum. 60(5):1508-18, 2009.
Study Completion
A-31
3b
Induction of expression of profibrotic cytokines and growth factors in normal human peripheral blood monocytes by gadolinium contrast agents.
Could the presence of inflammatory cells, shown to be present in ESRD, predispose to / increase the risk of NSF with all agents?
Article being prepared
3b
Investigate the effects of Dotarem, Prohance, Optimark, Magnevist on human monocytes, macrophages and fibroblasts in
Could the presence of inflammatory cells, shown to be present in ESRD, predispose to / increase the
Studies completed. Article in progress.
Study vitro. 4
Study Description
Questions Addressed risk of NSF with all agents? What effect do GBCA have on fibroblasts compared to GdCl3?
Publication Status
Study Completion
To investigate effect of free gadolinium (in the form of soluble concentrations of GdCl3), and GBCAs (Omniscan, Magnevist, Multihance, Dotarem, Prohance, Optimark) on human fibroblasts in vitro.
Edward M, Quinn JA, Mukherjee S, Jensen, M-BV, Jardine AG, Mark PB and Burden AD. Gadodiamide contrast agent 'activates' fibroblasts: a possible cause of nephrogenic systemic fibrosis. J Pathol. 214 (5): 584-593, 2008 Abstract presented to ECR (Vienna March 2009)
Completed
Identification of fibrotoc and inflammatory factors elevated in NSF blood post-Omniscan administration.
Is there a similar response between GBCA? Is free gadolinium the only risk factor for NSF? Effect of Dotarem, Prohance, Optimark, Magnevist pending
A-32
Paper in preparation. Ongoing. Not Yet Published
Are components found in the blood / serum of NSFs involved in the development of NSF? Are the factors found in NSF blood and serum the same as those released from inflammatory and fibrotic cells in vitro?
Study 5
Study Description Effect of free gadolinium and GBCAs on human skin organ cultures in vitro.
Questions Addressed Establish the direct effects of gadolinium species on human whole skin organ cultures.
Publication Status Varani J, DaSilva M, Warner RL, OBrien MD, Barron AG, Johnson KJ, Swartz R. 2009. Effects of Gadolinium-Based MRI Contrast Agents on Human Skin in Organ Culture and Human Skin Fibroblasts. Investigative Radiology. 44: 74-81 Bhagavathula N, DaSilva M, Aslam MN, Dame MK, Warner RL, Xu Y, Fisher GJ, Johnson KJ, Swartz R, Varani J. Regulation of Collagen Turnover in Human Skin Fibroblasts Exposed to a Gadolinium-Based Contrast Agent. Invest Radiol. 44(8):433-9, 2009.
Study Completion
Completed
Genotypic analysis of biopsy and blood samples from patients with normal renal function, and ESRD with and without NSF
Establish mechanism of NSF / markers of susceptibility to NSF
A-33
Create an expression profiling database on fibrocytes from normals, NSFs and intra Pulmonary Fibrosis (iPF) Create an expression profiling database of fibrocytes before and after exposure to different GBCAs
Do specific gene expression profiles exist and can these be linked etiologically to the pathologic properties of fibrocytes in vivo? Do GBCA alter gene expression patterns and are these patterns associated with the potential pathologic role of fibrocytes in NSF?
Initiated in March 2009 Ongoing.
Not Yet Published
Study 7
Study Description Study of the effect of GBCA incubated in human serum. Serum from normal subjects and serum from patients with End Stage Renal Disease (ESRD) with and without dialysis.
Questions Addressed To evaluate the behaviour of GBCA in pathologically relevant human serum samples
Publication Status Studies in Progress
Study Completion Ongoing. Not Yet Published
A-34
APPENDIX F
Letter to Healthcare Professionals
A-35
Important Drug Warning for Gadolinium-Based Contrast Agents

Magnevist (gadopentetate dimeglumine) Injection MultiHance (gadobenate dimeglumine) injection, 529 mg/mL Omniscan (gadodiamide) Injection OptiMARK (gadoversetamide) Injection ProHance (Gadoteridol) Injection, 279.3 mg/mL
September 12, 2007 Dear Healthcare Professional, The manufacturers of gadolinium-based contrast agents would like to inform you of important revisions to the prescribing information for the products listed in alphabetical order above. Gadolinium-based contrast agents are approved by the U.S. Food and Drug Administration (FDA) for use in magnetic resonance imaging (MRI). Post-marketing reports show that the use of these agents increases the risk of the development of a serious medical condition called Nephrogenic Systemic Fibrosis (NSF), in patients with acute or chronic severe renal insufficiency (glomerular filtration rate <30mL/min/1.73m2) and patients with renal dysfunction due to the hepato-renal syndrome or in the perioperative liver transplantation period. NSF leads to excessive formation of connective tissue in the skin and internal organs. NSF is progressive and may be debilitating or fatal. As of today, the FDA has received reports of over 250 cases of NSF after administration of gadolinium-based contrast agents. As a result of these NSF cases, the package inserts of all gadolinium-based contrast agents have been revised to include the following Boxed Warning and update to the WARNINGS section.
A-36
BOXED WARNING:
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate <30mL/min/1.73m2), or acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration (See WARNINGS).
WARNING: Nephrogenic Systemic Fibrosis (NSF)

Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency (glomerular filtration rate <30mL/min/1.73m2) and in patients with acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadolinium-based contrast agent in order to enhance the contrast agents elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure. Post-marketing reports have identified the development of NSF following single and multiple administrations of gadolinium-based contrast agents. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was gadodiamide (Omniscan), followed by gadopentetate dimeglumine (Magnevist), and gadoversetamide (OptiMARK). NSF has also developed following sequential administrations of gadodiamide with gadobenate dimeglumine (MultiHance) and gadoteridol (ProHance.) The number of post-marketing reports is subject to change over time and may not reflect the true proportion of cases associated with any specific gadolinium-based contrast agent. The extent of risk for NSF following exposure to any specific gadolinium-based contrast agent is unknown and may vary among the agents. Published reports are limited and predominantly estimate NSF risks with gadodiamide. In one retrospective study of 370 patients with severe renal insufficiency who received gadodiamide, the estimated risk for
Page 2
A-37
development of NSF was 4% (J Am Soc Nephrol 2006;17:2359). The risk, if any, for the development of NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent prior to any readministration. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION).
Further Information The complete prescribing information for Magnevist, MultiHance, Omniscan, OptiMARK and ProHance, as revised, is enclosed. The package inserts for the Magnevist, MultiHance, OptiMARK and ProHance pharmacy bulk packages have not been included in this mailing. These pharmacy bulk package inserts contain the same new safety information as the package inserts for these products. If you require further information regarding any of these products, information is available on the manufacturers website or by calling the manufacturers product information telephone number, as indicated below.
Product Magnevist MultiHance Omniscan OptiMARK ProHance Sponsor Bayer HealthCare Pharmaceuticals Inc. Bracco Diagnostics Inc. GE Healthcare Mallinckrodt Inc. Bracco Diagnostics Inc. Phone 1-888-842-2937 (option 4) 1-800-257-5181 (option 2) 1-800-654-0118 (option 2) 1-888-744-1414 (option 2) 1-800-257-5181 (option 2) Web www.imaging.bayerhealthcare.com www.bracco.com www.amershamhealthus.com/omniscan www.imaging.mallinckrodt.com www.bracco.com
Additional information on NSF is available from the FDA website (http://www.fda.gov/cder/drug/infopage/gcca/qa_200705.htm). We are working with the FDA and other regulatory authorities worldwide to learn more about the occurrence of this disease after the administration of gadolinium-based contrast agents. We urge healthcare professionals to report adverse event information to the respective manufacturer of the product suspected of the adverse event, as indicated below:
Product Magnevist MultiHance Omniscan OptiMARK ProHance
Sponsor Bayer HealthCare Pharmaceuticals Inc. Bracco Diagnostics Inc. GE Healthcare Mallinckrodt Inc. Bracco Diagnostics Inc.
Phone 1-888-842-2937 (option 1) 1-800-257-5181 (option 1) 1-800-654-0118 (option 2) 1-888-744-1414 (option 2) 1-800-257-5181 (option 1)
Page 3
A-38
Also, healthcare professionals may report adverse event information to the FDAs MedWatch program by phone (1-800-FDA-1088); on line (https://www.accessdata.fda.gov/scripts/medwatch); or by downloading Form 3500 at http://www.fda.gov/medwatch/getforms.htm and sending it to MedWatch by fax (1-800-FDA-0178) or by mail (5600 Fishers Lane, Rockville, MD 20852-9787). Sincerely, Bayer HealthCare Pharmaceuticals Inc. Bracco Diagnostics Inc.
E. Paul MacCarthy, M.D. Vice President, Head U.S. Medical Affairs
Alberto Spinazzi, M.D. Senior Vice President, Group Medical and Regulatory Affairs
GE Healthcare
Mallinckrodt Inc.
Larry Bell, M.D. Vice President, Global Head of Regulatory and Pharmacovigilance
Herbert Neuman, M.D. Vice President, Clinical and Regulatory Affairs
Page 4
A-39
APPENDIX G
Omniscan Package Insert
A-40
1160526 USA
ONC-2S-OSLO
HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all of the information needed to use OMNISCAN safely and effectively. See full prescribing information for OMNISCAN. OMNISCANTM (gadodiamide) Injection for Intravenous Use Initial U.S. Approval: 1993
WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF)
See full prescribing information for complete boxed warning.
NOT FOR INTRATHECAL USE

Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits (5.4). Gadolinium-based contrast agents (GBCAs) increase risk of NSF in patients with (5.2): o acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73m2), or o acute renal insufficiency of any severity due to hepato-renal syndrome or in perioperative liver transplantation period. In these patients, avoid use of GBCAs unless diagnostic information is essential and not available with non-contrast enhanced MRI (5.2). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle, and internal organs (5.2).
NSF
RECENT MAJOR CHANGES

Boxed Warning: Nephrogenic Systemic Fibrosis (NSF) Warnings and Precautions: Hypersensitivity Reactions (5.1) Warnings and Precautions: NSF (5.2) Warnings and Precautions: Acute Renal Failure (5.3) Warnings and Precautions: Not for Intrathecal Use (5.4) 9/2007 9/2007 9/2007 9/2007 9/2007
INDICATIONS AND USAGE

OMNISCAN is a gadolinium-based contrast agent for diagnostic magnetic resonance imaging (MRI) indicated for intravenous use to: Visualize lesions with abnormal vascularity in the brain, spine, and associated tissues (1.1) Facilitate the visualization of lesions with abnormal vascularity within the thoracic, abdominal, pelvic cavities, and the retroperitoneal space (1.2)
DOSAGE AND ADMINISTRATION

CNS Adults and Pediatrics; 2-16 years of age: 0.2 mL/kg (0.1 mmol/kg) (2.1, 2.4) Body Adults and Pediatrics; 2-16 years of age: Kidney: 0.1 mL/kg (0.05 mmol/kg) Intrathoracic, intra-abdominal, and pelvic cavities: 0.2 mL/kg (0.1 mmol/kg) (2.2, 2.4)
DOSAGE FORMS AND STRENGTHS

Sterile aqueous solution for intravenous injection; 287 mg/mL (3)
CONTRAINDICATIONS
None (4)
WARNINGS AND PRECAUTIONS

Anaphylactoid and other serious hypersensitivity reactions including fatal reactions have occurred particularly in patients with history of allergy or drug reactions. Monitor patients closely for need of emergency cardiorespiratory support (5.1).
2007 General Electric Company - All rights reserved.
A-41
OMNISCAN (gadodiamide) Injection
Nephrogenic Systemic Fibrosis (NSF) has occurred in patients with severe renal insufficiency. Higher than recommended dosing or repeat dosing appears to increase the risk (5.2). Acute renal failure has occurred in patients with preexisting renal insufficiency. Use the lowest necessary dose of OMNISCAN and evaluate renal function in these patients (5.3).
ADVERSE REACTIONS
The most frequent adverse reactions ( 3%) observed during OMNISCAN adult clinical studies were nausea, headache, and dizziness (6.1) Serious or life-threatening reactions include: cardiac failure, arrhythmia and myocardial infarction (6.1, 6.3) To report SUSPECTED ADVERSE REACTIONS, contact GE Healthcare at 1-800-6540118 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2007
FULL PRESCRIBING INFORMATION: CONTENTS* WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) 1
1.1 1.2
INDICATIONS AND USAGE

CNS (Central Nervous System) Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions)
2
2.1 2.2 2.3 2.4 2.5
DOSAGE AND ADMINISTRATION

CNS (Central Nervous System) Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions) Dosage Chart Dosing Guidelines Repeat Dosing
3 4 5
5.1 5.2 5.3 5.4 5.5 5.6
DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS

Hypersensitivity Reactions Nephrogenic Systemic Fibrosis Acute Renal Failure Not for Intrathecal Use Impaired Visualization of Lesions Detectable with Non-contrast MRI Laboratory Test Findings
6
6.1 6.2 6.3
ADVERSE REACTIONS
Clinical Studies Experience (Adults) Clinical Studies Experience (Pediatrics) Postmarketing Experience
7 8
8.1 8.3 8.4 8.5 8.6
DRUG INTERACTIONS USE IN SPECIFIC POPULATIONS

Pregnancy Nursing Mothers Pediatric Use Geriatric Use Renal/Hepatic Impairment
10 11 12 13 14
OVERDOSAGE DESCRIPTION CLINICAL PHARMACOLOGY NONCLINICAL TOXICOLOGY CLINICAL STUDIES
12.2 Pharmacodynamics 12.3 Pharmacokinetics 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 14.1 CNS (Central Nervous System) 14.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions)
2
A-42
16 17
HOW SUPPLIED/STORAGE AND HANDLING PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the full prescribing information are not listed.
FULL PRESCRIBING INFORMATION WARNING: NOT FOR INTRATHECAL USE and NEPHROGENIC SYSTEMIC FIBROSIS (NSF) NOT FOR INTRATHECAL USE
Inadvertent intrathecal use of OMNISCAN has caused convulsions, coma, sensory and motor neurologic deficits [see Warnings and Precautions (5.4)].
NSF
Gadolinium-based contrast agents increase the risk for NSF in patients with: acute or chronic severe renal insufficiency (glomerular filtration rate < 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. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle, and internal organs. Screen all patients for renal dysfunction by obtaining a history and laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration [see Warnings and Precautions (5.2)].
1 1.1
INDICATIONS AND USAGE CNS (Central Nervous System)
OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to visualize lesions with abnormal vascularity (or those thought to cause abnormalities in the blood-brain barrier) in the brain (intracranial lesions), spine, and associated tissues [see Clinical Studies (14.1)].
1.2
Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions)
OMNISCAN is a gadolinium-based contrast agent indicated for intravenous use in MRI to facilitate the visualization of lesions with abnormal vascularity within the thoracic (noncardiac), abdominal, pelvic cavities, and the retroperitoneal space [see Clinical Studies (14.2)].
2 2.1
DOSAGE AND ADMINISTRATION CNS (Central Nervous System)
Adults: The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection. An additional 0.4 mL/kg (0.2 mmol/kg) can be given within 20 minutes of the first dose [see Dosage and Administration (2.3)]. Pediatric Patients (2-16 years): The recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) administered as a bolus intravenous injection [see Dosage and Administration (2.3)].
2.2
Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions)
Adult and Pediatric Patients (2-16 years of age): For imaging the kidney, the recommended dose of OMNISCAN is 0.1 mL/kg (0.05 mmol/kg). For imaging the intrathoracic (noncardiac), intra-abdominal, and pelvic cavities, the recommended dose of OMNISCAN is 0.2 mL/kg (0.1 mmol/kg) [see Dosage and Administration (2.3)].
A-43
2.3
Dosage Chart
BODY WEIGHT kg lb 12 26 14 31 16 35 18 40 20 44 22 48 24 53 26 57 28 62 30 66 40 88 50 110 60 132 70 154 80 176 90 198 100 220 110 242 120 264 130* 286 PEDIATRIC 0.05 0.1 (mmol/kg) VOLUME (mL) 1.2 2.4 1.4 2.8 1.6 3.2 1.8 3.6 2 4 2.2 4.4 2.4 4.8 2.6 5.2 2.8 5.6 3 6 4 8 5 10 6 12 7 14 8 16 0.05 ADULTS 0.1 0.2 (mmol/kg) VOLUME (mL) 8 16 10 20 12 24 14 28 16 32 18 36 20 40 22 44 24 48 26 52
4 5 6 7 8 9 10 11 12 13
*The heaviest patient in clinical studies weighed 136 kg.
2.4
Dosing Guidelines
Inspect OMNISCAN visually for particulate matter and discoloration before administration, whenever solution and container permit. Do not use the solution if it is discolored or particulate matter is present. Draw OMNISCAN into the syringe and use immediately. Discard any unused portion of OMNISCAN Injection. To ensure complete delivery of the desired volume of contrast medium, follow the injection of OMNISCAN with a 5 mL flush of 0.9% sodium chloride, as provided in the Prefill Plus needle-free system. Complete the imaging procedure within 1 hour of administration of OMNISCAN.
2.5
Repeat Dosing
Sequential use during the same diagnostic session has been studied in adult CNS use only. If the physician determines repeat dosing is required in non-CNS imaging in adults or pediatric patients, renal function should be normal and the time interval between repeat doses should be at least 7 hours to allow for clearance of the drug from the body [see Clinical Pharmacology (12.3)].
3 4
None.
DOSAGE FORMS AND STRENGTHS CONTRAINDICATIONS WARNINGS AND PRECAUTIONS Hypersensitivity Reactions
Sterile aqueous solution for intravenous injection; 287 mg/mL.
5 5.1
Anaphylactoid and anaphylactic reactions, with cardiovascular, respiratory and/or cutaneous manifestations, resulting in death have occurred. If such a reaction occurs, stop OMNISCAN Injection and immediately begin appropriate therapy. Observe patients closely, particularly those with a history of drug reactions, asthma, allergy or other hypersensitivity disorders, during and up to several hours after OMNISCAN Injection.
5.2
Nephrogenic Systemic Fibrosis [see Boxed Warning]
Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with acute or chronic severe renal insufficiency (glomerular filtration rate < 30 mL/min/1.73m2) and in patients with acute renal insufficiency of
4
A-44
any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period. In these patients, avoid use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with noncontrast enhanced MRI. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a gadoliniumbased contrast agent in order to enhance the contrast agents elimination. The usefulness of hemodialysis in the prevention of NSF is unknown. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a gadolinium-based contrast agent and the degree of renal function impairment at the time of exposure. Postmarketing reports have identified the development of NSF following single and multiple administrations of gadolinium-based contrast agents. These reports have not always identified a specific agent. Where a specific agent was identified, the most commonly reported agent was gadodiamide (Omniscan), followed by gadopentetate dimeglumine (Magnevist) and gadoversetamide (OptiMARK). NSF has also developed following the sequential administrations of gadodiamide with gadobenate dimeglumine (MultiHance) or gadoteridol (ProHance). The number of postmarketing reports is subject to change over time and may not reflect the true proportion of cases associated with any specific gadolinium-based contrast agent. The extent of risk for NSF following exposure to any specific gadolinium-based contrast agent is unknown and may vary among the agents. Published reports are limited and predominantly estimate NSF risks with gadodiamide. In one retrospective study of 370 patients with severe renal insufficiency who received gadodiamide, the estimated risk for development of NSF was 4% (J Am Soc Nephrol 2006;17:2359). The risk, if any, for the development of NSF among patients with mild to moderate renal insufficiency or normal renal function is unknown. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent prior to any readministration [see Clinical Pharmacology (12.2) and Dosage and Administration (2)].
5.3
Acute Renal Failure
In patients with renal insufficiency, acute renal failure requiring dialysis or worsening renal function have occurred, mostly within 48 hours of OMNISCAN Injection. The risk of renal failure may increase with increasing dose of gadolinium contrast. Use the lowest necessary dose of contrast and evaluate renal function in patients with renal insufficiency. Acute renal failure was observed in < 1% of patients in OMNISCAN clinical studies [see Adverse Reactions (6)]. OMNISCAN is cleared by glomerular filtration. Hemodialysis also enhances OMNISCAN clearance [see Use in Specific Populations (8.5, 8.6)].
5.4 5.5
Not for Intrathecal Use Impaired Visualization of Lesions Detectable with Noncontrast MRI
Inadvertent intrathecal use of OMNISCAN has occurred and caused convulsions, coma, sensory and motor neurologic deficits.
Paramagnetic contrast agents such as OMNISCAN might impair the visualization of lesions which are seen on the non-contrast MRI. This may be due to effects of the paramagnetic contrast agent, or imaging parameters. Exercise caution when OMNISCAN MRI scans are interpreted in the absence of a companion non-contrast MRI.
5.6
Laboratory Test Findings
Asymptomatic, transitory changes in serum iron have been observed. The clinical significance is unknown. OMNISCAN interferes with serum calcium measurements with some colorimetric (complexometric) methods commonly used in hospitals, resulting in serum calcium concentrations lower than the true values. In patients with normal renal function, this effect lasts for 12-24 hours. In patients with decreased renal function, the interference with calcium measurements is expected to last during the prolonged elimination of OMNISCAN. After patients receive OMNISCAN, careful attention should be used in selecting the type of method used to measure calcium.
ADVERSE REACTIONS
Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
5
A-45
6.1
Clinical Studies Experience (Adults)
In clinical studies 1160 patients were exposed to OMNISCAN. The most frequent adverse reactions were nausea, headache, and dizziness that occurred in 3% or less of the patients. The majority of these reactions were of mild to moderate intensity. The following adverse reactions occurred in 1% or less of patients: Application Site Disorders: Injection site reaction. Autonomic Nervous System Disorders: Vasodilation. Body as a Whole-General Disorders: Anaphylactoid reactions (characterized by cardiovascular, respiratory, and cutaneous symptoms), fever, hot flushes, rigors, fatigue, malaise, pain, syncope. Cardiovascular Disorders: Cardiac failure, rare arrhythmia and myocardial infarction resulting in death in patients with ischemic heart disease, flushing, chest pain, deep thrombophlebitis. Central and Peripheral Nervous System Disorders: Convulsions including grand mal, ataxia, abnormal coordination, paresthesia, tremor, aggravated multiple sclerosis (characterized by sensory and motor disturbances), aggravated migraine. Gastrointestinal System Disorders: Abdominal pain, diarrhea, eructation, dry mouth/vomiting, melena. Hearing and Vestibular Disorders: Tinnitus. Liver and Biliary System Disorders: Abnormal hepatic function. Musculoskeletal System Disorders: Arthralgia, myalgia. Respiratory System Disorders: Rhinitis, dyspnea. Skin and Appendage Disorders: Pruritus, rash, erythematous rash, sweating increased, urticaria. Special Senses, Other Disorders: Taste loss, taste perversion. Urinary System Disorders: Acute reversible renal failure. Vision Disorders: Abnormal vision.
6.2
Clinical Studies Experience (Pediatrics)
In the 97 pediatric patients in CNS studies with OMNISCAN [see Clinical Studies (14.1)] and the 144 pediatric patients in published literature, the adverse reactions were similar to those reported in adults.
6.3
Postmarketing Experience
Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during the postmarketing use of OMNISCAN: Nervous System Disorders: Inadvertent intrathecal use causes seizures, coma, paresthesia, paresis. General Disorders: Nephrogenic Systemic Fibrosis (NSF) [see Warnings and Precautions (5.2)].
7 8 8.1
DRUG INTERACTIONS USE IN SPECIFIC POPULATIONS Pregnancy
Specific drug interaction studies have not been conducted.
Pregnancy Category C: OMNISCAN has been shown to have an adverse effect on embryo-fetal development in rabbits at dosages as low as 0.5 mmol/kg/day for 13 days during gestation (approximately 0.6 times the human dose based on a body surface area comparison). These adverse effects are observed as an increased incidence of flexed appendages and skeletal malformations which may be due to maternal toxicity since the body weight of the dams was reduced in response to OMNISCAN administration during pregnancy. In rat studies, fetal abnormalities were not observed at doses up to 2.5 mmol/kg/day for 10 days during gestation (1.3 times the maximum human dose based on a body surface area comparison); however, maternal toxicity was not achieved in these studies and a definitive conclusion about teratogenicity in rats at doses above 2.5 mmol/kg/day cannot be made. Adequate and well controlled studies in pregnant women have not been conducted. OMNISCAN should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus.
A-46
8.3
Nursing Mothers
It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, exercise caution when administering OMNISCAN to a nursing woman.
8.4
Pediatric Use
The safety and efficacy of OMNISCAN at a single dose of 0.05 to 0.1 mmol/kg have been established in pediatric patients over 2 years of age based on adequate and well controlled studies of OMNISCAN in adults, a pediatric CNS imaging study, and safety data in the scientific literature. However, the safety and efficacy of doses greater than 0.1 mmol/kg and of repeated doses have not been studied in pediatric patients. Pharmacokinetics of OMNISCAN have not been studied in pediatrics. The glomerular filtration rate of neonates and infants is much lower than that of adults. The pharmacokinetics volume of distribution is also different. Therefore, the optimal dosing regimen and imaging times in patients under 2 years of age have not been established.
8.5
Geriatric Use
In clinical studies of OMNISCAN, 243 patients were between 65 and 80 years of age while 15 were over 80. No overall differences in safety or effectiveness were observed between these patients and younger patients. Other reported clinical experience has not identified differences in response between the elderly and younger patients, but greater sensitivity in the elderly cannot be ruled out. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal or cardiac function, and of concomitant disease or other drug therapy. OMNISCAN is excreted by the kidney, and the risk of toxic reactions to OMNISCAN may be greater in patients with impaired renal function [see Warnings and Precautions (5.3)]. Because elderly patients are more likely to have decreased renal function, select dose carefully and consider assessment of renal function before OMNISCAN use.
8.6
Renal/Hepatic Impairment
Dose adjustments in renal or hepatic impairment have not been studied. Caution should be exercised in patients with impaired renal insufficiency [see Warnings and Precautions (5.2, 5.3)].
10
OVERDOSAGE
Clinical consequences of overdose with OMNISCAN have not been reported. The minimum lethal dose of intravenously administered OMNISCAN in rats and mice is greater than 20 mmol/kg (200 times the recommended human dose of 0.1 mmol/kg; 67 times the cumulative 0.3 mmol/kg dose). OMNISCAN is dialyzable.
11
DESCRIPTION
OMNISCAN (gadodiamide) Injection is the formulation of the gadolinium complex of diethylenetriamine pentaacetic acid bismethylamide, and is an injectable, nonionic extracellular enhancing agent for magnetic resonance imaging. OMNISCAN is administered by intravenous injection. OMNISCAN is provided as a sterile, clear, colorless to slightly yellow, aqueous solution. Each 1 mL contains 287 mg gadodiamide and 12 mg caldiamide sodium in Water for Injection. The pH is adjusted between 5.5 and 7.0 with hydrochloric acid and/or sodium hydroxide. OMNISCAN contains no antimicrobial preservative. OMNISCAN is a 0.5 mol/L solution of aqua[5,8-bis(carboxymethyl)-11-[2(methylamino)-2-oxoethyl]-3-oxo-2,5,8,11-tetraazatridecan-13-oato (3-)-N5, N8, N11, O3, O5, O8, O11, O13] gadolinium hydrate, with a molecular weight of 573.66 (anhydrous), an empirical formula of C16H28GdN5O9xH2O, and the following structural formula:
O
Gd O N
H N CH3 xH2O
O N H
O H H O O
H 3C
A-47
Pertinent physicochemical data for OMNISCAN are noted below:
PARAMETER
Osmolality (mOsmol/kg water) Viscosity (cP) Density (g/mL) Specific gravity @ 37C @ 20C @ 37C @ 25C @ 25C 789 2 1.4 1.14 1.15
OMNISCAN has an osmolality approximately 2.8 times that of plasma at 37C and is hypertonic under conditions of use.
12
CLINICAL PHARMACOLOGY
12.1 Pharmacodynamics
In magnetic resonance imaging, visualization of normal and pathologic tissue depends in part on variations in the radiofrequency signal intensity. These variations occur due to: changes in proton density; alteration of the spin-lattice or longitudinal relaxation time (T1); and variation of the spin-spin or transverse relaxation time (T2). OMNISCAN is a paramagnetic agent with unpaired electron spins which generate a local magnetic field. As water protons move through this local magnetic field, the changes in magnetic field experienced by the protons reorient them with the main magnetic field more quickly than in the absence of a paramagnetic agent. By increasing the relaxation rate, OMNISCAN decreases both the T1 and T2 relaxation times in tissues where it is distributed. At clinical doses, the effect is primarily on the T1 relaxation time, and produces an increase in signal intensity. OMNISCAN does not cross the intact blood-brain barrier and, therefore, does not accumulate in normal brain or in lesions that do not have an abnormal blood-brain barrier (e.g., cysts, mature postoperative scars). However, disruption of the blood-brain barrier or abnormal vascularity allows accumulation of OMNISCAN in lesions such as neoplasms, abscesses, and subacute infarcts. The pharmacokinetic parameters of OMNISCAN in various lesions are not known. There is no detectable biotransformation or decomposition of gadodiamide.
12.3 Pharmacokinetics
The pharmacokinetics of intravenously administered gadodiamide in normal subjects conforms to an open, two-compartment model with mean distribution and elimination half-lives (reported as mean SD) of 3.7 2.7 minutes and 77.8 16 minutes, respectively. Gadodiamide is eliminated primarily in the urine with 95.4 5.5% (mean SD) of the administered dose eliminated by 24 hours. The renal and plasma clearance rates of gadodiamide are nearly identical (1.7 and 1.8 mL/min/kg, respectively), and are similar to that of substances excreted primarily by glomerular filtration. The volume of distribution of gadodiamide (200 61 mL/kg) is equivalent to that of extracellular water. Gadodiamide does not bind to human serum proteins in vitro. Pharmacokinetic and pharmacodynamic studies have not been systematically conducted to determine the optimal dose and imaging time in patients with abnormal renal function or renal failure, in the elderly, or in pediatric patients with immature renal function.
13
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Long term animal studies have not been performed to evaluate the carcinogenic potential of gadodiamide. The results of the following genotoxicity assays were negative: in vitro bacterial reverse mutation assay, in vitro Chinese Hamster Ovary (CHO)/Hypoxanthine Guanine Phosphoribosyl Transferase (HGPT) forward mutation assay, in vitro CHO chromosome aberration assay, and the in vivo mouse micronucleus assay at intravenous doses of 27 mmol/kg (approximately 7 times the maximum human dose based on a body surface area comparison). Impairment of male or female fertility was not observed in rats after intravenous administration three times per week at the maximum dose tested of 1.0 mmol/kg (approximately 0.5 times the maximum human dose based on a body surface area comparison).
A-48
14
CLINICAL STUDIES
14.1 CNS (Central Nervous System)

OMNISCAN (0.1 mmol/kg) contrast enhancement in CNS MRI was evident in a study of 439 adults. In a study of sequential dosing, 57 adults received OMNISCAN 0.1 mmol/kg followed by 0.2 mmol/kg within 20 minutes (for cumulative dose of 0.3 mmol/kg). The MRIs were compared blindly. In 54/56 (96%) patients, OMNISCAN contrast enhancement was evident with both the 0.1 mmol/kg and cumulative 0.3 mmol/kg OMNISCAN doses relative to non-contrast MRI. In comparison to the non-contrast MRI, increased numbers of brain and spine lesions were noted in 42% of patients who received OMNISCAN at any dose. In comparisons of 0.1 mmol/kg versus 0.3 mmol/kg, the results were comparable in 25/56 (45%); in 1/56 (2%) OMNISCAN 0.1 mmol/kg dose provided more diagnostic value and in 30/56 (54%) the cumulative OMNISCAN 0.3 mmol/kg dose provided more diagnostic value. The usefulness of a single 0.3 mmol/kg bolus in comparison to the cumulative 0.3 mmol/kg (0.1 mmol/kg followed by 0.2 mmol/kg) has not been established. OMNISCAN as a single 0.1 mmol/kg dose was evaluated in 97 pediatric patients with a mean age of 8.9 (2-18) years referred for CNS MRI. Postcontrast MRI provided added diagnostic information, diagnostic confidence, and new patient management information in 76%, 67%, and 52%, respectively, of pediatrics.
14.2 Body (Intrathoracic [noncardiac], Intra-abdominal, Pelvic and Retroperitoneal Regions)

OMNISCAN was evaluated in a controlled trial of 276 patients referred for body MRI. These patients had a mean age of 57 (9-88) years. Patients received 0.1 mmol/kg OMNISCAN for imaging the thorax (noncardiac), abdomen, and pelvic organs, or a dose of 0.05 mmol/kg for imaging the kidney. Pre- and post-OMNISCAN images were evaluated blindly for the degree of diagnostic value rated on a scale of remarkably improved, improved, no change, worse, and cannot be determined. The postcontrast results showed remarkably improved or improved diagnostic value in 90% of the thorax, liver, and pelvis patients, and in 95% of the kidney patients. In a dose ranging study 258 patients referred for body MRI received OMNISCAN 0.025, 0.05, 0.1 mmol/kg. The lowest effective dose of OMNISCAN for the kidney was 0.05 mmol/kg.
16
HOW SUPPLIED/STORAGE AND HANDLING
OMNISCAN (gadodiamide) Injection is a sterile, clear, colorless to slightly yellow, aqueous solution containing 287 mg/mL of gadodiamide in rubber stoppered vials and prefilled syringes. OMNISCAN is supplied in the following sizes: 5 mL fill in 10 mL vial, box of 10 (NDC 0407-0690-05) 10 mL vial, box of 10 (NDC 0407-0690-10) 15 mL fill in 20 mL vial, box of 10 (NDC 0407-0690-15) 20 mL vial, box of 10 (NDC 0407-0690-20) 50 mL vial, box of 10 (NDC 0407-0690-55) 10 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-12) 15 mL fill in 20 mL prefilled syringe, box of 10 (NDC 0407-0690-17) 20 mL prefilled syringe, box of 10 (NDC 0407-0690-22) Prefill Plus needle-free system OMNISCAN 15 mL, box of 10 (NDC 0407-0691-62) Contains: OMNISCAN 15 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe Prefill Plus needle-free system OMNISCAN 20 mL, box of 10 (NDC 0407-0691-63) Contains: OMNISCAN 20 mL fill in 20 mL Single Dose Prefilled Syringe and 5 mL 0.9% Sodium Chloride Injection, USP I.V. Flush Syringe Protect OMNISCAN from strong daylight and direct exposure to sunlight. Do not freeze. Freezing can cause small cracks in the vials, which would compromise the sterility of the product. Do not use if the product is inadvertently frozen. Store OMNISCAN at controlled room temperature 20-25C (68-77F); excursions permitted to 15-30C (59-86F) [see USP].
A-49
17
PATIENT COUNSELING INFORMATION
Patients receiving OMNISCAN should be instructed to inform their physician if they: are pregnant or breast feeding, or have a history of renal disease, convulsions, asthma or allergic respiratory disorders, or recent administration of gadolinium-based contrast. Gadolinium-based contrast agents increase the risk for NSF among patients with acute or chronic severe renal insufficiency or acute renal insufficiency due to the hepato-renal syndrome. This risk may increase with repetitive or higher than recommended doses of a gadolinium-based contrast agent. Instruct patients at increased risk for NSF to contact their physician if they develop burning, itching, swelling, scaling, hardening and tightening of the skin; red or dark patches on the skin; stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet; pain deep in the hip bones or ribs; or muscle weakness.
GE Healthcare
Distributed by GE Healthcare Inc. Princeton, NJ 08540 U.S.A. Manufactured by GE Healthcare AS Oslo, Norway OMNISCAN is a trademark of GE Healthcare. GE and the GE Monogram are trademarks of General Electric Company. OptiMARK is a registered trademark of Mallinckrodt Inc. Magnevist is a registered trademark of Berlex Laboratories, Inc. MultiHance is a registered trademark of Bracco International B.V. ProHance is a registered trademark of Bracco Diagnostics Inc. Revised December 2007 ONC-2S-OSLO
1160526 USA 10
A-50

CRDAC B1 06 GE Omniscan

Enviado por

Dados do documento

Título original

Direitos autorais

Formatos disponíveis

Compartilhar este documento

Compartilhar ou incorporar documento

Opções de compartilhamento

Você considera este documento útil?

Este conteúdo é inapropriado?

Direitos autorais:

Formatos disponíveis

CRDAC B1 06 GE Omniscan

Enviado por

Direitos autorais:

Formatos disponíveis

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Omniscan Safety Review Advisory Meeting Briefing Document

AVAILABLE FOR PUBLIC DISCLOSURE WITHOUT REDACTION

GE Healthcare Inc. 101 Carnegie Center Princeton, NJ, 08540-6231

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Type of renal failure and stage of chronic renal failure.................................... 34 Trending

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

7.5 7.6 7.7 8

CONCLUSIONS ..........................................................................................................49 REFERENCE LIST ...................................................................................................... 51

Figure 3 The characteristic appearance of NSF....................................................................... 19

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Table 4 Table 5 Table 6 Table 7 Table 8 Table 9 Table 11

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

OMNISCAN HISTORY, UTILIZATION, AND SAFETY NDA Approval

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

*Japan: number of vials sold between January 1998 to January 2009

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Figure 1 Distribution volume relative to NSF cases reported

% of Total in Reported US and EU Countries

Cases not proportional to volume sold

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Overall Safety of Omniscan

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

See Nervous system disorders (Table 8)

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009

Immune system reactions

Available for public disclosure without redaction

Omniscan Advisory Meeting Briefing Document GE Healthcare

Version 1.0 November 3, 2009