ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Bracco Diagnostics Inc. Advisory Committee Briefing Document MultiHance (gadobenate dimeglumine) ProHance (gadoteridol) Table of Contents List of Tables .................................................................................................................................. 5 List of Figures................................................................................................................................. 6 Executive Summary........................................................................................................................ 7 1 Introduction ......................................................................................................................... 12 1.1 MultiHance and ProHance: Chemical Names, Structures and Approved Indications .................................................................................................................... 12 1.2 Properties of Gadolinium-based Contrast Agents........................................................ 13 1.3 Problem Statement ....................................................................................................... 15 2 Evidence of Gd Retention in Brain and Body Tissues ........................................................ 16 2.1 Gd Retention in Brain Tissues...................................................................................... 16 2.1.1 Tissue-Sample Studies .......................................................................................... 16 2.1.1.1 Nonclinical, Tissue-Sample Studies............................................................... 16 2.1.1.1.1 Levels of Elemental Gd in Brain Tissues Following Exposure to Different GBCAs in Healthy Rats........................................................... 16 2.1.1.1.2 Levels of Elemental Gd in Brain Tissues Following Exposure to Different GBCAs in Animals with Impairment of Renal Function ........ 22 2.1.1.1.3 Possible Chemical Forms of Gd Complexes Retained in Brain Tissues Following Exposure to Different GBCAs.................................. 23 2.1.1.1.4 Retention of Gd Complexes in Brain Tissues Over Time....................... 27 2.1.1.1.5 Conclusions on Gd Retention Data from Nonclinical Tissue- Sample Studies........................................................................................ 28 2.1.1.2 Clinical Tissue-Sample Studies...................................................................... 29 2.1.1.2.1 Levels of Elemental Gd in Brain Tissues................................................ 29 2.1.1.2.2 Distribution and Speciation of Gd Deposits ........................................... 33 2.1.1.2.3 Conclusions on Gd Retention Data from Clinical Tissue-Sample Studies..................................................................................................... 33 2.1.2 Imaging Studies..................................................................................................... 36 2.1.2.1 Available Evidence ........................................................................................ 36 2.1.2.2 Conclusions on Data from Imaging Studies................................................... 40 2.1.3 Overall Conclusions on Gd Retention in Brain Tissues........................................ 40 2.2 Gd Retention in Body Tissues...................................................................................... 43 2.2.1 Nonclinical Studies ............................................................................................... 43 2.2.1.1 Levels of Elemental Gd in Skin Following Exposure to Different GBCAs in Healthy Rats ................................................................................. 43 2.2.1.2 Retention of Gd in Skin Tissues Over Time .................................................. 44 2.2.1.3 Levels of Elemental Gd in Skin Following Exposure to Different GBCAs in Animals with Impairment of Renal Function............................... 46 2.2.1.4 Levels of Elemental Gd in Bone Tissues (Femur) Following Exposure to Different GBCAs in Healthy Rats ............................................................. 46 2.2.1.5 Levels of Elemental Gd in Bone Tissues (Femur) Following Exposure to Different GBCAs in Animals with Impairment of Renal Function........... 47 Document ID: BDI-REP-A62075.17-MH_PH Br-B084686-2.0 Page 2 of 104 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Bracco Diagnostics Inc. Advisory Committee Briefing Document MultiHance (gadobenate dimeglumine) ProHance (gadoteridol) 2.2.1.6 Levels of Elemental Gd in Liver Following Exposure to Different GBCAs in Healthy Rats ................................................................................. 48 2.2.1.7 Levels of Elemental Gd in Liver Following Exposure to Different GBCAs in Animals with Impairment of Renal Function............................... 49 2.2.1.8 Levels of Elemental Gd in Kidney Following Exposure to Different GBCAs in Animals with Impairment of Renal Function............................... 49 2.2.1.9 Levels of Elemental Gd in Kidney Following Exposure to Different GBCAs in Animals with Impairment of Renal Function............................... 50 2.2.1.10 Conclusions on Gd Retention Data in Body Tissues from Nonclinical Tissue-Sample Studies ................................................................................... 51 2.2.2 Clinical Studies ..................................................................................................... 52 2.2.2.1 Retention in Bone........................................................................................... 52 2.2.2.2 Retention in Skin............................................................................................ 53 2.2.2.3 Retention in Liver .......................................................................................... 55 2.2.2.4 Conclusions on Clinical Body Tissue-Sample Studies .................................. 56 2.2.3 Overall Conclusions on Gd Retention in Body Tissues........................................ 57 3 Assessment of Potential Toxicity of Gd Retained in Brain and Body Tissues ................... 58 3.1.1 Acute Neurotoxicity Studies of GBCAs ............................................................... 58 3.1.2 Assessment of Neurotoxicity of Retained Gd Complexes in Animal Studies ................................................................................................................... 60 3.1.3 Assessment of Neurotoxic Potential from Clinical Data ...................................... 62 3.1.3.1 Post-mortem Tissue-Sample Studies.............................................................. 62 3.1.3.2 Imaging and Epidemiologic Studies .............................................................. 62 3.1.4 Conclusions on Potential Effects of Gd Retention in Brain Tissues..................... 68 3.2 Assessment of Potential Effects of Gd Retention in Body Tissues.............................. 69 3.2.1 Nonclinical Evidence ............................................................................................ 69 3.2.2 Clinical Evidence .................................................................................................. 71 3.2.2.1 Nephrogenic Systemic Fibrosis (NSF)........................................................... 71 3.2.2.2 Non-NSF Delayed Adverse Events................................................................ 73 3.2.2.2.1 Gadolinium-associated Plaques .............................................................. 74 3.2.2.2.2 Gadolinium-Deposition Disease ............................................................. 74 3.2.2.2.3 Case Report of Joint Contractures in a Patient with Normal Renal Function .................................................................................................. 76 3.2.2.3 Conclusions on Potential Effects of Gd Retention in Body Tissues.............. 77 4 Benefit-Risk Balance of MultiHance .................................................................................. 78 4.1 Assessment of Clinical Benefit Provided by MultiHance............................................ 79 4.1.1 MRI of the CNS .................................................................................................... 80 4.1.2 MR Angiography (MRA)...................................................................................... 80 4.1.3 Conclusion on the Clinical Benefit of MultiHance in the Approved Indications ............................................................................................................. 81 4.2 Assessment of Clinical Benefit Provided by ProHance ............................................... 81 4.3 Risk Assessment........................................................................................................... 82 4.3.1 Immediate-type Hypersensitivity Reactions ......................................................... 82 4.3.2 Nephrogenic Systemic Fibrosis (NSF).................................................................. 83 Document ID: BDI-REP-A62075.17-MH_PH Br-B084686-2.0 Page 3 of 104 ADVISORY COMMITTEE BRIEFING MATERIALS: AVAILABLE FOR PUBLIC RELEASE Bracco Diagnostics Inc. Advisory Committee Briefing Document MultiHance (gadobenate dimeglumine) ProHance (gadoteridol) 4.3.3 Gadolinium Retention in Brain and Body Tissues................................................ 83 4.3.3.1 T1 Hyperintensity in Deep Brain Areas......................................................... 83