NOT FOR DISTRIBUTION MRI for Technologists: MRI Technologists: MRI for the learner Contrastto the Safety introduces technologist.theof control direct manyunder ofculmination thethe MRIis Afactors examination successful images. diagnostic T OVERVIEW currentinformation regarding expiration dates. Please goto and relevance. accuracy This ma refresh to looking basein MR imaging. knowledge their those for review a provide to classroom as well as examinations, board review the take to augment technology to on- and designed instruction These are radiologic (MRI). imaging units of resonance needs magnetic of the field the in working and/or meet entering technologists to designed MRI Safety Agent Contrast Technologists for MRI to recognize and respond to the most common adverse patient reactions. mostcommonadversethetopatient respond and recognizeto exaanatomyand pathology, m- normal of visualization ,media contrast After Note: EDUCAT for for (ASRT) American beenRadiologic programofTechnologists approvedSociety has by the This he skill of the technologist is the single most important factor in obtaining good important quality singlefactor most is the technologist hethe of skill 1.0 • • • completing this educational material, the reader willto: reader ablethe educational material,be completing this

for Technologists Ter

hour ARRT Category A continuing education credit. continuing ARRTCategoryhourA Define the different types of MRI contrast media typesMRIof contrast different the Define media administration media contrast patient MRIrespondreactions mostcommonto adverse theand to Recognize MRIofexaminations types appropriate different contrast specificmedia for Determine terial terial will bereviewed continuedfor IONAL CREDIT IONAL ms in in ms

tdns n poesoas planning professionals and students

www.icpme.us bold

thein glossary. can be found throughout material this ie riig o radiologic for training site

s tann program training a is

for up- for

to -

date

Expiration Rel June

June specific agents, andhow agents, specific ease 1, different types ofdifferenttypes

2012 20 Date Date

MR I I NOT FOR DISTRIBUTION FAC NMR Pittsburgh Institute. The CommunityVirginiaand North College, Mason James University, of a graduate is Schrack Mr. Postgraduat for Center Technical ConsiderationsTechnologists: of MRI and BodyApplicationsof MRI with Intern MD,and- co 1997; David with Stroller, author,contributing 1996; authorHeofthe is Manager. includingadvancedhigh roles, severalin RadiologicalMr.Consultants, Fairfax joining to Prior RegistryMRIofAmericanExaminersTechnologists. Boardof the of the onalsoHe serves clinical procedures. MRand CommunityCollege, physics teaching Virginia Northern Faculty serves Instructor for asAdjunct also Schrack Mr. Consults, Radiological MRDevelopmentofFairfax at as Manager Educationand Technical currently serving While VA Fairfax, Consultants Radiological Fairfax MRDevelopment Education and Manager, Technical Tho receive credit andonline. completed must be credit receive with recommendations of other authorities. contraindications on dangers in use, review of any applicable manufacturer’s product information, and comparison suggested in this activity should not be used by clinicians without evaluation of their patient’s conditions and possible patient management. Any procedures, medications, or other courses of diagnosis or treatment discussed or their own professional development. The information presented in this activity is not meant to serve as a guideline for Participants have an implied responsibility to use the newly acquired information to enhance patient outcomes and DISCLAIMER activity time complete isto this Estimated CREDIT RECEIVE TO HOW • • • • • •

mas Schrack, BS, ARMRITSchrack, mas

UL accessible through the course link in yourinlink account. course through the accessible ataccount yourto in Log entireactivity. the Read www.icpme.us at courseonline enrolltheand in evaluation, posttest theorderaccess to In of credit. of ahow certificate print on to youwillinstructions passing a of receive grade, receipt Upon upthree times. to take test maythe You credit. receiveto be 75%istoeligibleleast atrequired of passing grade A TY BIOGRAPHY TY

. e Medical Education, 2006 and 2009,2006 and respectively. MedicalEducation,

sonance Imaging inMagnetic Orthopaedics Imaging Resonance

Echo Planar An ApplicationsImaging: Guide,

www.icpme.us

author of two modules in the series titled titled authorofseriesthe intwo modules - field applications development as 1.5T Marketingas1.5T applications development field 1.0 1.0

hour. The posttest and evaluation are required to requiredevaluationare to posttest and hour. The

to complete the posttest and evaluation, posttestcompleteand the to

Schrack was employed by GE Healthcarewas byemployedGE Schrack

& Medicine Sports

GE Healthcare, GE MRI for for MRI ii ational ational NOT FOR DISTRIBUTION TED BY ANEDUCATION BY TED SUPPOR BY SPONSORED NY Bronx, MedicineCollegeof Einstein Albert Medical Center Montefiore Neurosurgery ClinicalofRadiologyand Professor Neuroradiology of Director Bello, Jacqueline For otherwisenoted. VA, unless Fairfax, Consultants, FairfaxofRadiological courtesy Allimages ACKNOWLEDGMENTS MEdSchleelein, H. Lisa Phoenix,BS Victoria McLean,MSLinda MD,FACRBello, Jacqueline ARMRIT BS, Schrack, Tom activity:CEof content this the related to havewithinterests partnercommercial spouse/life their devicesthey orproducts or to andhave advisors, managers planners, The faculty, following partner. orandplannersspouse/life managers, their advisors, or faculty notNIH; eg, (2) the agencies, (1) governmental exemptions: withthe services or following healthcare goods producing commercial that interest. of services or CEproduct oftheto relating controlcontent theopportunity to and interestthe commercial withrelationshipa aboth when individual has exists an financial (COI) interestof conflict A ainterest. commercial of interest proprietarybusiness specific and a not healthcare inimprovements quality or promotes withhighproviding- learners to ICPMEcommitted is DISCLOSURE INTEREST OF CONFLICT

insightful review insightful

MD, FACRMD,

of the material, special thanks go to: thanks go special material, the of

-

for - profit organizations; and (3) CE honoraria received by the CEbythe andreceived organizations; (3) honoraria profit

AL

A commercial interest is defined as any proprietary entitydefinedasany is proprietary Ainterest commercial

GRANTFROM

quality continuing education (CE) that that (CE)education continuing quality

NO relationships or relationships relationships orNOrelationships iii

NOT FOR DISTRIBUTION agents agents Most contrast agentsderivedare from Mostcontrast MEDIA CONTRAST OF PROPERTIES PARAMAGNETIC willto: reader ablethe educational material,be completing this After Safety Agent Contrast most widely used paramagnetic agentswidelyparamagnetic used most dysprosium, andcopper also dysprosium, MRI by MRI imagi resonance contrast magnetic media ofto introduction The INTRODUCTION MR arterialandvenousanatomyand pathology. of visualization and inflammation, orinfection,abscesses, secondaryasortumors, primary such lesions increasenormal conspicuityanatomy, theof of and characterization identification the tocontribute havethey : clinicalagentsuse Contrast widespread itself. vasculaturethe including Table 1 Table I I • • •

contrast agents can be divided into different classescan different agentsdivided be contrast into Oral Oral agents pool Blood - Hepatocyte chelates) (gadolinium extracellular Nonspecific

Define the different typesMRof different the Define Determine Determine media administration media Recognize are increas . Classes of MRI contrast agents. contrast MRI of Classes . agents for gastrointestinal imaging gastrointestinal for agents

nonspecific ing specific agents specific

specific contrast media appropriate contrast specificmedia for and respond and to the intrinsic contrast between contrast intrinsicthe

, Class of Agent of Class extracellular

agents have paramagnetic properties. haveparamagnetic

ent reactions to MRI contrast contrast MRI patireactions to ent mostcommonadverse the

agents. Gadolinium paramagnetic

ther Other metal . I I contrast media contrast

, vascularizedand tissue nonvascularized ions

substances

( different , suchasiron, manganese, , chelates Table

ng revolutionized field the 1 ; the majority of paramagnetic of the; majority

). types of MRof types

are the best known and theareknown best

Administration Intravenous Intravenous Intravenous Method of Oral I I examinations

improve

of of

NOT FOR DISTRIBUTION intravascular and extracellularand spaces. intravascular gadolinium extracellular electrons. unpairedorbital of paramagneticof common feature A ing closelyapproach ing Protons ion. gadoliniumthe vicinityof thein increase ngth stre agents magnetic field contrast Paramagnetic space.intracellular intothe chelates extracellular gadoliniumnonspecific entryof bodyprevent interact with the locally altered magnetic field in that facilitates a manner locally magnetic field altered withthe interact I chelate. gadolinium resulting relaxation, time demonstrated on- demonstrated T1 intensity signalincreased in the results onofprotonsthat ionadjacent effect the gadolinium the is it visualized MRI;is directly not on moleculeitself contrast agents. The enhancement positive demonstrating fundamentally different from CT or from different fundamentally directly attenuate the x the attenuate directly negative contrast enhancement contrast negative imaging, T2* the perfusion MRbrain ascertain applications such ofIn chelate. gadolinium administration the after minutes several systems normal inrenal collecting seen void be signalthat may explains the shift rises. This a n normal n dvantage. dvantage. images. weighted demonstrated on T1 increasedsignal intensity the in that results ion on adjacent protons effect of the gadolinium visualized on MRI; it is the itselfnot is directly molecule contrast The

of protons of tissues In th , increased signal. Thus, T1 signal. Thus, increased causing tissue protons to appear brighter on appearT1 protonsto brighter causing tissue is setting is that absorb the contrast absorb the that in weighted images. weighted

shorteni - raybeam chelate - , the gadolinium chelate serves as a susceptibility agent asusceptibility chelateas serves gadolinium the ,

After ng of the T1 relaxation time of protons in the vicinity of the inthe vicinityof theprotons relaxationofof T1time ng the (darker signal).(darker rapidly equilibrates betweenthe rapidlyequilibrates . aparamagnetic substance intravenous administration, an intravenousadministration, radiographic

substances

re used to of clinicalused properties areto gadolinium shortening

Paramagnetic gadolinium chelate. In most most tissues chelate.In gadolinium counteract darker, appearto tissues causes shortening shortening, T2 protons. tissueUnlike T1 of times shorten theand to T2* actT2 also chelate. chelate. extdoseofmmol/kg0.1 standard of injection a afterpredominates intravenous effect predominate as the concentration of gadolinium chelate of concentrationas gadolinium the predominate Normal living cells in the the in cells living Normal In this way, paramagnetic MR contrast agents areMRagents contrast paramagnetic way,this In

- agent, agent, g shortening paramagnetic agentsparamagneticas also are known shortening

However,the T2*

yangiograph ispresence the ing adolinium chelates shortenchelates adolinium

the positive enhancement effect of enhancementeffect the positive the agents , suchas , , including, contrast agents contrast - weighted ima weighted

shortening effect begins to to begins effect shortening

, chelate gadolinium

space. intracellular the gadoliniumchelates into extracellular nonspecific of entry prevent body the in cells living Normal gadolinium c gadolinium

racellular gadolinium gadolinium racellular rapidl (T2 star) star) (T2 , the T1 the

suchasiodine ges the ongitudinal ongitudinal ,

- T1 relaxation T1 and produc shortening shortening relaxation relaxation helates

2 | 2 ing Page ,

that

NOT FOR DISTRIBUTION for for specificity limited serumalbuminhuman weaklytoand exhibits binds althoughit agent, extracellular into into eight The Chemical and Properties Physical Gadavist™ Eovist® Ablavar® ProHance® OptiMARK Omniscan™ MultiHance® Magnevist® are States United ( and knownvendorsby severalbyare chelates manufactured Gadolinium A other than for the central nervous systemcentralnervous thanthe for other Ablavar administered for routine clinical use. clinicaluse. routine administered for MRof contrast volume small relativelywithdue beenthe likelyto observed MRagents, not reactions adverse oflower incidence a with remain neutral. agents electricallynonionic I albumin, onic agents dissociate into positively and negatively charged ions in the bloodstream, whilein bloodstream, ions the the intopositivelydissociatecharged negatively agents and onic Table 2). Table nother FDA nother 2. Table hepatocytes. However, Brand Name • • • three

I Macrocy N ® onic

onionic

ing keep ,

™ ™ List of gadolinium of List

currently currently categories:

The The a

: Magnevist,MultiHance Eovist, Ablavar, : non - approved contrastapproved nonspecific extracellular extracellular gadolinium nonspecific

c : Omniscan, : - extracellular blood pool extracellularblood lic

gadoxetate disodium gadoxetate (Gd gadoteridol (Gd gadoversetamide (Gd gadodiamide (Gd dimeglumine gadobenate (Gd dimeglumine gadopentetate gadobutrol trisodium gadofosveset it in circulationitin . Gadavist

FDA (as opposed to linear): Gadavist, ProHance Gadavist, linear): opposedto (as

- - - - - HP DTPA DTPA BOPTA) DTPA) - approved gadoli approved - DO3A) - based contrast agents approved by the FDA as of Jun 2012 Jun of as FDA the by approved agents contrast based TM

Generic Name Generic - -

at this time time this at BMEA) BMA) OptiMARK , ,

Eovist

agent,

Ablavar is FDA Ablavaris

®

o , , f Gadolinium f

Magnevist

MultiHance there is no FDA clearance for MultiHance for indications MultiHanceindications is no clearancethere FDA for for

nium

agent .

Although nonionic CT contrast agents are associated arecontrastagents CT Althoughnonionic than - based contrast agents (GBCAs) can be dividedcanbe agents (GBCAs) based contrast , completes the list. This agent list. completesthe, This - ionic ® approved for approved for March 2011 March 2008 July June 1988 June July 2008 July 1992 November 1999 December 1993 January 2004 December , Omniscan ,

® chelates approved for intravenous use in theapproveduse chelates intravenous for , is often categorized as a nonspecioftencategorizedasa is , - Based ContrastBased Date of FDA CT contrast Approval

TM

usein , OptiMARK

agents, this phenomenon has this agents, aortoiliac Bayer Healthcare Bayer (Wayne, NJ) (Wayne, Healthcare Bayer NJ) (Wayne, Healthcare Bayer ( Imaging Medical Lantheus NJ) (Princeton, Inc. Diagnostics, Bracco MO) Louis, (St. Inc. Mallinckrodt, WI) (Waukesha, Healthcare GE NJ) (Princeton, Inc. Diagnostics, Bracco NJ) (Wayne, N. N. Agents Billerica, MA Billerica, various TM

, and ProHance and , binds to serum binds serum to Manufacturer

MRangiography 1.

brand namesbrand

)

3 | 3 fic fic Page

®

. . .

NOT FOR DISTRIBUTION , which consists of the which ,space consists fluid agents, extracellular The free gadolinium ion isiontoxic gadolinium The free ainchain- togetherlinked atomsarewhere the arrangement, bond linear Macrocyclic relaxivity clinicaldoses. at standard tissues human molecules that come into close proximity to the gadolinium ion. Both T1 Both the T1 ion. proximity gadolinium intoclose to that come molecules MRIby thesystem. produced the body for long periods of time, and result in and longresult time, bodyof periods for the Because g the elimination. Since elimination. andbiodistribution influencesitsbut itonly notmakes ion safe gadolinium the of Chelation Table 3. Table Lantheus Medical Imaging Medical Lantheus must be bound ion must be gadolinium Bayer Healthcare Bayer Bayer Healthcare Bayer Bayer Healthcare Bayer GE Healthcare GE Manufacturer Brand Name/ Brand OptiMARK MultiHance Omniscan Magnevist Gadavist™ ProHance

Ablavar® Gadolinium Covidien Eovist® Bracco Bracco (r adolinium c adolinium 2 ) agents consist agents are are

™ ™ ® ™

® facilitated facilitated ®

Magnevist, ProHance, Omniscan,

-

b

ased ased they equilibrate rapidly after intravenous injection within the extracellular within the injection intravenous equilibrate rapidlyafter they ontrast agents are are agents ontrast

c ontrast ontrast

by paramagnetic contrast agents, but T1 effectswithinpredominate butagents, T1 contrast byparamagnetic ing ing atomssurround of dimeglumine gadopentetate gadobenate dimeglumine gadobenate C ; it can it ; ontrast agentsalsoontrast (Gd a interstitial space and the blood pool blood spaceand interstitialthe gadoversetamide (Gd (Gd to a chelating to gents gents gadofosveset Gadodiamide (Gd (Gd gadoxetate gadoteridol - gadobutrol - - DTPA Generic

- DTPA - becom HP - BOPTA) - and molecular structure. molecular and DTPA) paramagnetic they paramagnetic -

DO3A) BMEA) BMA) e

cardiac

sequest

ligand

a chemically a

facilitate OptiMARK

- - ered in liver, spleen, andspleen,bone, liver, in ered and neurotoxicity and suchasDTPA MRA Aortoiliac MRA

amplify the external magnetic field external magnetic field amplify the proton relaxation within proton relaxationwater Indication CNS/Body CNS/Body CNS/Liver -

bound metal ion, as opposed to a as opposed to metal ion, bound , , Liver CNS CNS CNS Eovist and Gadavist and Eovist

.

(pentetic acid). (pentetic relaxivity . To To .

like fashion ( fashion like prevent prevent toxicity Structure/Charge - Non - Non Ionic, Linear Ionic, Ionic, Linear Ionic, Ionic, Linear Ionic, Ionic, Linear Ionic, Macrocyclic Macrocyclic Molecular Molecular

(r Ionic, Ionic, ionic, Linear ionic, 1 ) and T2 )

are are Table 3 Table

remain in remain 4 | 4 Linear Page

, , ).

NOT FOR DISTRIBUTION , MultiHance,extracellular, degree andviaeliminated biliary excretion. by hepatocytes up filtration MultiHance is is MultiHance interstitial spaces in neural tissue. tissue. neural in spaces interstitial the canenter agents these disrupted, - blood wherethe areas blood- normal the cross donot agents contrast based ium gadolin approved currently The receiving chemotherapy or chemotherapy receiving pat for exercised be should Caution liver. the in interactions bythe eliminated partially are Eovist and MultiHance Since liver. the eliminatedbythenormal other50%is agents: kidneysvia the from contain full information. full contain inserts package The disorders. metabolic underlying certain is potential for drug for potential is , ,

withthe 50%of dominantly an extracellular agent;however,3% extracellular dominantly pre an brain barrier. In In barrier. brain - to - drug drug brain barrier is barrier brain 2,3

dose eliminated within one to twohours.toeliminatedwithin one dose liver

ients ients with with , there there

agents are eliminated from the body by the kidneys via glomerular viabodybyglomerular the eliminated kidneys are the from agents - Courtesy of GE Medical Systems patella the to superior and head tibial and tibia inthe F surrounding the fluid posterior and inferior to the patella (arrow). patella the to inferior and posterior fluid the surrounding head postcontrast A igure 3. igure

infection bony indicating ,

Sagittal T1W image of the knee the image of T1W Sagittal . Note the increased intensity of the tibia and tibial tibial and tibia the of intensity increased the Note .

With exceptionthe of With (circle) with with (circle) – (arrows)

Eovist is is Eovist 5% of the injected dose is taken doseis taken injected the5%of glomerular filtration glomerular filtration

Maimonides Medical Center Courtesy of Mark Flyer, MD - breath T1 postcontrast Figure 2 demonstr image T1 Figure 1 . . carcinoma cell an demonstrates kidney right the through (circle) and enhancement enhancement and (circle) B . (B) .

eliminated differently eliminated increased fluid posterior posterior fluid increased

. . (Right) Eovist, and to alesser Eovist, and to

ates brain metastases. brain ates Same slice location location slice Same (Left) (Left) through the brain brain the through .

(A) Axial Axial

A Sagittal Sagittal enhancing renal renal enhancing bnormal signal signal bnormal 5 | 5 and50%via postcontrast postcontrast Page held

image image

NOT FOR DISTRIBUTION

Gadolinium chelates are used in the evaluationofthe arein chelates used Gadolinium necessarilyconstruedagentnot be should contrast contrast - mid the in later developed were media 1950s; early the in imaging contrast radiographic for introduced were compounds Ionic years. many - pre agents these of nonionic and ionic both as available also are imaging CT and angiography radiographic in used media contrast Iodinated ions. into dissociate not do and bloodstream, - zero a have nonionic Conversely, bloodstream. the in or water in ions charged negatively or positively into dissociate that agents , discussed previously As Ionic and Nonionic Contrast and Ionic Courtesy of Mark Flyer, MD runoff peripheral demonstrating extremities Figure 4 • • •

primary tumors and( tumors metastases primary infectious and inflammatory processes ( and processes inflammatory infectious vascular anatomy and( pathology anatomy vascular - . Gadolinium . enhanced MR studies in pediatric patientspediatric in enhancedMR studies net charge, remain electrically neutral in water or the the or water in neutral electrically remain charge, net date the clinical use of MRI contrast agents by agents contrast MRI of use clinical the date - enhanced MR angiograms of the lower the lower of angiograms MR enhanced , Maimonides Medical Center ionic contrast media are pharmaceutical pharmaceutical are media contrast ionic Media

nonionic radiographic contrast contrast radiographic nonionic to Figures - . Figures4 la te1980s.

pharmaceutical agents agents pharmaceutical

Figure 3 Figure

1 and

nearly all organ systems organ allnearly and compounds. Most Most compounds. er the age of age two.theunder as dangerouspatient. the to as 2 5 ) ) ) ) perfusion imaging, andimaging, perfusion imaging, perfusion brain pass first viabilityand myocardial studies important includes constitute Off FDA. FDA. the cificallybyspe approved applications for developedclinicalmany physicianshave other and radiologists years,the Over Maimonides Medical Center Courtesy of Mark Flyer, MD system. aortoiliac the of MRA enhanced F -l

igure Off abel

Such applicationsSuch for the followingfor - : n MRI usean labelof MR angiography, an array of arrayof an

, 5. 5. u

off

widely used se Gadolinium - label

GBCAs 6 | 6

. This . This use Page : : -

not not

NOT FOR DISTRIBUTION Early clinical research on Earlyclinicalresearch The The twosolutions. theof concentration in equalization is The dissolvedresult ofnet concentration substance. higher anofarea of area to loweran concentration water, from as Osmosis Osmolality inaddressed material later this are events of gadolinium infusion contrast agents. Consider the following twopoints:Consideragents. following the contrast onwithradiographicexperience based MR ofagents contrast characteristics safety predict valid be to areIt may contrastunderstood. poorlynot media iodinated events from adverse leading biologicalto mechanisms agents. and ionicThe to MR contrast nonionic extrapolate dothesenotadverse However, lower events. with a of findings incidence wereassociated measured in units of osmoles per kilogram of water of , per osmoles of unitskilogram in measured inwhen compoundplaced solution. the isOsmolalityis result and osmose abilityto ns to MR to incidenceadverseof ns reactio actual The or milliosmoles per kilogram of waterof , kilogram per milliosmoles or 0.07% 6% al et contrast materials. Cochran iodinated nonionicor ionic for – osmolality 8% for ionic iodinated contrast agents, 0.2% for nonionic iodinated contrast agents, andagents, iodinated nonioniccontrast 0.2% agents, for iodinated ioniccontrast 8% for

for gadolinium for 1. 2.

is is primarily based on differences inon differences based primarily is nonionic ia distinctioncontrast med and radiographic betweenionic practice, the In intrathecally administeredis agent wheniodinated iscontrast charge an important of absence iodinated contrast media. contrast iodinated comparedtostructure molecular different havestrikingly agents contrast MRI isagentwithlowionic that osmolality. contrast (loxaglate Hexabrix™ example, Foralways anddoes not true. betweenchargeosmolalityhold relationship However, lowarethis hyperosmolar,while areosmolar. agents nonionic agents possibility v defined as the diffusion of solvent molecules, suchmolecules, solventasof diffusion defined the s Osmotic Load Osmotic s

of a chemical compound is chemical a ofcompound

- of charged molecules binding to calcium. Most ionic radiographic contrast contrast calcium.radiographicMostionic charged to moleculesbinding of - is is based MRI contrast agents.basedMRI contrast based MR contrast agentbased MR contrast related to the numberparticles theofthat to related

and may be significant during intracoronary injection due theto duringintracoronaryinjection significant be may and iodinated

meglumine and ioxaglate sodium, Covidienioxaglate sodium, and meglumine)

contrast agents revealed that low agents that revealed contrast mOsm/kg. . a measure o a measure osmolality s I

4 contrast material is substantially lower than that that substantially is than material lower contrast is supported byotherstudiesis supported

This low rate of adverselowof events following rate This Osm/kg f its

and not differences in charge.in differences The not and

, , found adverse reaction rates ofadverse rates found reaction - contrast materials. contrast nonionic iodinated or ionic for that lower thansubstantially material is contrast adverse reactions to MRI The actual incidence of osmolar

is aradiographicis . 5-

nonionic agentsnonionic 7 Ac ute adverse ute 7 | 7 Page

NOT FOR DISTRIBUTION - two a for permitted amount the of 10,000ths) (four 0.4% than less and mother the to given dose total the of 0.0004% to translates (Mag dimeglumine gadopentetate administered of 0.04% than less that found have Studies risk. the outweighs far benefit expected the if only pregnancy in used be should chelates gadolinium practice, In recirculated. being effectively fetus, bythe swallowed then and fluid amniotic the into excreted are agents wherethe bladder, fetal the in accumulate and placenta the cross mother practice a “pump and dump” protocol for breast milk for 24 hours following injection. following hours 24 for milk breast for protocol dump” and “pump a practice mother concerned remains mother the if However, milk. breast in present material contrast of amount small the ingest to mother breastfeeding a of child the for safe is it that state (FDA) Administration Drug and Food the and (ACR) Radiology of College American the both from guidelines the Therefore, mother. the to administration GBCA following infant breastfeeding a in reaction allergic of instances reported no been have there as theoretical only remains it far thus but infant, the in reaction allergic of risk theoretical a is There pregnancy. in chelates gadolinium of safety and use the addressed have studies Several Gad of Use media. contrast iodinated of that to compared small relatively is agents MRcontrast of dose effective the because is this Again, scanning. CT for used agents contrast iodinated of those to compared small are 0.2ml/kg of dose clinical standard a at loads osmotic the ), (MultiHance mOsm/kg 1970.0 0.688 from widely ranges agents contrast gadolinium of osmolality the Although patients. into injected volume byactual agent of volume unit per ca is load Osmotic – 275 is adults in osmolarity serum blood Normal blood. of that as osmolality same the have ideally should patients to intravenously administered solution chemical a shifts, fluid dangerous potentially avoid To terchangeably. in used often are terms the and minimal, is osmolarity and osmolality between difference the body, human normal the of fluids biological dilute the In (mOsm/L). solution of liter per milliosmoles or osmoles Osmolarity nevist) is excreted into human breast milk. The amount of contrast ingested by the infant infant the by ingested contrast of amount The milk. breast human into excreted is nevist)

olinium Chelates in Pregnancy in Chelates olinium is a related factor that is measured in units of of units in measured is that factor related a is lculated by multiplying the milliosmoles milliosmoles the bymultiplying lculated about the contrast material passing through breast milk, it is recommended that the the that recommended is it milk, breast through passing material contrast the about year - old child. child. old mOsm/kg (Eovist mOsm/kg 300 mOsm/L. mOsm/L. 300

) to to

indicating central pontine m pontine central indicating lesion enhancing small a demonstrates image in a 40- a in image Figure 6 Courtesy of Bayer Healthcare

. Axial T1W contrast T1W Axial . year - old male male old 8-

yelinolysis 11 8 | 8 12,13 - All GBCAs GBCAs All enhanced enhanced Page

.

NOT FOR DISTRIBUTION 4. Table clinicaldose standard The dialysis. peritoneal or hemodialysis on those including function, renal impaired with patients in used be therefore can and materials contrast iodinated of nephrotoxicity the have not do chelates gadolinium doses, clinical recommended at administered When ensure to flush saline a by their concentrations are higher higher are concentrations their Gadavist™ Eovist® Ablavar® ProHance® OptiMARK Omniscan™ MultiHance® Magnevist® only. use intravenous for approved in shown are chelates gadolinium various of doses Recommended Dosing blood return, and proper saline flush following contrast administration. contrast following flush saline proper and return, blood good of assurance access, intravenous of placement careful including technique, injection proper but but serious, more rarely are and pain or burning mild with transient usually are extravasation of Effects site. injection the surrounding tissue into leaks agent the of volume sufficient a if tissue soft injure mOsm/kg nausea, taste alteration, and vertigo. vertigo. and alteration, taste nausea, headache, are agents all for reactions adverse commonlyreported most The next. the to population patient one from greatly varies chelates gadolinium all for reactions adverse of incidence reported The dose. reduced the at Gadavist using images postcontrast can include can Brand Name

Dosing and administration of GBCAs of administration and Dosing a

, nd Administration nd ™ ™

and Ablavar 825.0 Ablavar825.0 and

inflammation, ulceration, or skin necrosis. Extravasation is easily preventable through through preventable easily is Extravasation necrosis. skin or ulceration, inflammation, gadobutrol (Gd gadoversetamide (Gd dimeglumine gadobenate gadoxetate disodium gadoxetate (Gd gadoteridol (Gd gadodiamide (Gd dimeglumine gadopentetate gadofosveset trisodium gadofosveset ------DTPA BOPTA) HP - DTPA DTPA)

the entire dose of the contrast agent is agent contrast the of dose entire the for Gadavist, Eovist, and Ablavar and Eovist, Gadavist, for - DO3A)

mOsm/kg

BMEA) BMA) — Generic

Name Gadavist, has Gadavist,

I njection of gadolinium of njection

o Extravasation

—

. 14

. reduced be can dosage the

an osmolality of osmolality an f gadolinium contrast agents can potentially canpotentially agents contrast gadolinium f -

based contrast agents should be followed followed be should agents contrast based Clinical Dose Clinical 0.12ml/kg Standard

0.2ml/kg ml/kg 0.1 0.2ml/kg 0.1ml/kg 0.2ml/kg 0.2ml/kg 0.2ml/kg than lower are

pushed through the IV tubing. IV the through pushed 1603.0 Table 4 Table

mOsm/kg Figures 6 Figures . These agents are are agents These . other GBCAs. other 110lbs = 13.2ml = 110lbs 110lbs = 10ml = 110lbs 110lbs = 10ml = 110lbs 110lbs = 10ml = 110lbs 110lbs = 10ml = 110lbs 10ml = 110lbs 110lbs = 5ml = 110lbs 110lbs = 5ml = 110lbs Example , Eovist , Weight and 7 9 | 9

Because Because 0.688 are are

Page

NOT FOR DISTRIBUTION Eovist hepatocellular carcinoma hepatocellular and hyperplasia(FNH) with suspected nodular focal patients arethese Clinically, suspectedwith or focal adults andknown incharacterize lesions detect to imaging Hepatocy for 1993 in wasdiamide,FDA (gado Healthcare) GE Omniscan Body AGENTS BODY GENERAL syringes contrast agents, Om contrast as well as cavities, pelvicabdominal withinand thoracic, lesionsthe noncardiac is is OptiMARK feces. comes at at patient Noncardiac Chest, Abdomen, and PelvisAbdomen, Contrast Media Chest,and Noncardiac a 0.1mmol/kgalso is dosage approvedSimilarly, urine. vascula withabnormal lesions l of visualization is indicated infor It 1999.use FDA for 0.1mmol/kg. patient weighing110lbs. patient excreted excreted pproximately also the injection site. the Omniscan • • •

-

specific contrast agents contrast specific OptiMARK

(gadoxetate disodium, Bayer Healthcare) was approved by the FDA in 2008 for liver2008 infor FDAHealthcare) Bayer disodium, wasbythe approved (gadoxetate

FDA approved for central nervous system imaging system nervous. central approvedFDA for in in - Hepatocyte pelvisabdomen,agents and chest, Noncardiac Oral contrast agents contrast Oral ages 2- ages for

deliver in loaded syringes instead of vials.loadedofinstead pre syringes te

(gadoversetamide, (gadoversetamide, central nervous system indications systemcentral nervous urine. -S

For example,For also also pecific Agents pecific 95% of gadoversetamide isexcreted of gadoversetamide 95% 16. Approved16. exact dosageand reduce exact

15 differs from other contrast agents in that i that incontrast agents other from differs includes

in in 16 The remaining The specific agentsspecific ni the retroperitoneal space. Like other thespace. retroperitoneal the scan

The majority ofis gadodiamide majority The

(HCC)

10m

is approved is f

specific bodyspecificindications

dosage Omof dosage

r are Covidien ity. Like Om ity. l . IV contrast is the dose for a is dose for the contrast IV 17

categorized into three categorizedthree into

contrast ) was approved by the wasbythe approved ) or adults and pediatric and adultsor

the risk risk the is n niscan iscan, Preloaded Preloaded excre . FDAapproval and of is is OptiMARK ted ted approved in : :

infection infection

the the

iver iver in groups

t t

:

lesion. enhancing the demonstrates Courtesy of Bayer Healthcare (B) Precontrast (A) 69- Figure 7 B A

year Postcontrast image image Postcontrast

- old male with lymphoma. with male old . Axial T1W in a T1W Axial . image. disease. | 10

Page

NOT FOR DISTRIBUTION Eovist is 0.025mmol/kg. For example, a 110lb patient requires only5m requires patient 110lb a example, For 0.025mmol/kg. is Eovist GI is an Imagent States. United the in use human approvedfor agent contrast oral MRI first wasthe Corp.) AlliancePharmaceutical (perflubron, GI® Imagent 1993, In practice. clinical in applied widely been has them of none FDA, bythe approved havebeen agents MRcontrast oral several Although Agents MR Oral ( hyperintense appear hepatocytes functioning without whilelesions hypointense, appear hepatocytes functioning with Liver lesions injection. after minutes 20 approximately occurs phase hepatocyte intracellular This intracellularly. byhepatocytes up taken selectively is contrast Follo creation. bile and cholesterol and metabolism, carbohydrate synthesis, protein in involved 70- comprising liver, the in type maincell the are Hepatocytes through of percent Fifty agent. contrast 0.1mmol/kg a for 10ml of dose typical more the gadolinium other most to compared dosing smaller for allows relaxivity Greater relaxivity. of degree high witha agent contrast linear ionic an is Eovist - T1 on lumen bowel the within void signal a produces GI Imagent aresult, As atom. bromine one and atoms market shortly after its approval. approval. its shortlyafter market the from withdrawn was and acceptance clinical gain to failed GI Imagent cost, high relatively its with Along administration. oral after rectum per leak to tendency unfortunate the has and rapidly Courtesy of Bayer Healthcare 9 Figure Eovi of uptake indicating hyperintense, increasingly is lesion The postcontrast. 8 Figure A ruling out HCC. The central region is unenhanced, consistent with the presence of a central scar typical of FNH. FNH. of typical scar central a of presence the with consistent unenhanced, is region central The HCC. out ruling typical of FNH and the biliary excretion into the common bile duct and duodenum. and duct bile common the into excretion biliary the and FNH of typical

wing injection, Eovist is quickly distributed into the extracellular space. Over time, 50% of the the of 50% time, Over space. extracellular the into distributed quickly is Eovist injection, wing

. . the kidneys the inert perfluorocarbon in which all of the hydrogen atoms have been replaced by fluorine fluorine by replaced havebeen atoms hydrogen the of allwhich in perfluorocarbon inert (Right) (Right) Coronal h Coronal - and T2 C oronal T1 hepatocytephase MIP 35 secondspost

epatocyte phase images post images phase epatocyte

and weighted images. Imagent GI moves through the gastrointestinal tract tract gastrointestinal the through moves GI Imagent images. weighted the other the

50% 50% B

through the liver the through - Eovist injection. (A) 10 minutes postcontrast. (B) 20 20 (B) postcontrast. minutes 10 (A) injection. Eovist - based contrast agents. The dose amount of of amount dose The agents. contrast based .

- 80% of its mass. They are directly directly are They mass. its of 80% Eovist injection. Note hyperenhancing mass mass hyperenhancing Note injection. Eovist st by functioning hepatocytes and and hepatocytes functioning by st l of contrast compared to to compared contrast of

Eovistisexcre Figure 8 Figure | 11

and minutes minutes Page ted ted 9 ) .

NOT FOR DISTRIBUTION and (B) Axial T Axial (B) FIESTA™ Coronal (A) agent contrast oral Figure Lumenhanc GastroMARK been distallyduodenum dilutedmoved as become they to beyond the tendency T1 wereprimarily citrate, GastroMARK There are several explanations for the limited utilization of oral MR contrast. OneoralMR utilization contrast. explanationslimited of severaltheare for There (Feridex to similaragentparticulate an iron is States. It United stilltheavailablein agent efficacy, which explains the continued use of “off the shelf” methods to ofshelf” the methods use “off continuedwhich explainsthe efficacy, B A

low discontinued. 10 Otsuka Otsuka

® signal on T2 signal . , Bayer Healthcare) Bayer , 2W fat 2W

Volumen e ® ™

- losson T1- signal intraluminal causes

( (manganese chloride (manganesechloride tetrahydrate Pharmaceutical - , AMAGPharmaceuticals ferumoxsil , suppressed image. image. suppressed - in - on signalT1 producedintraluminal agents bright that shortening ® used as a as used ®

the small bowel. small the - im weighted images. images. weighted age. age.

except that it is formulated for oral use. When administered orally,oraluse. administered is for thatit formulated except When positive Co. Ltd.) Co.

The

were approved as oral MR contrast agentsBoth1997.in oral wereMRapproved as contrast oating property ( coating highitsof - because bowel MRagenttheof whensmall imaging used for contrast an inexpensiveeffectivepositive be and shownto hasbeen agent.(Bracco)Volumen® contrast positive a asoftenusedin sulfate CT solutions barium whenusing effectivebecome of small has bowelthe MRimaging wall. bowel of involvement the or thickening, neoplastic abnormal inflammation, ofareas boweland the wallenhance agent intravenousserves to The contrast administration. chelate with intravenous gadolinium conjunction inMetamucil and used havebarium been dilute T1 intensitysignalon intraluminal lowproducing boweland the lumen distending draw thereby colon, into the waterto Metamucilserves also been used with some success. T usedsuccess. withsomebeen also contrast inon bowel theT1 lumen contrast negativeproduce to method effective reasonably ahasbeenbariumused as dilute example, For images. images. Metamucil images. clinical efficacy efficacy clinical , Bracco) ) and- T2 was approved in 1996 and is only1996 thewasinand oral approved

18

and FerriSel and of both agents agents both of weightedimages. Figure ® ( psyllium, Proctor & ProctorGamble psyllium,

10). signal intensity and bowelintensityand signal visualize

tz . B . ® was limited bya was limited 19 - oth products oth -

weighted images.Both weighted (ferricammonium and T2 20

ferumoxide

he he the bowelMR on the is is weighted images images weighted hypertonicity their - weighted | 12

limited limited Page have ) has has -

of of NOT FOR DISTRIBUTION here. here. click information, more For phase. arterial MIP 3D Coronal (C) state. steady venous MIP 3D Coronal (B) MIP. 3D of reformation 2D Coronal (A) disease. aortoiliac with Figure 11. B A

benefit of using a much lower concentration level. Lantheus Medical recommends a dosage of of dosage a recommends Medical Lantheus level. concentration lower much a using of benefit added the permitting protons, water for time relaxation T1 the decreases also mechanism C

Ablavar.com

57

- year

- old male male old

and vomiting. and generalabdominal complaints such as abdominal pain ornausea for used often less is imaging MR glands. adrenal or kidneys, pancreas, liver, the in lesions indeterminate of evaluation for is imaging MR example, For organs. specific on focused primarily have applications MR abdominal that is agents contrast MR oral of utilization limited the for reason Another bloodpool imagingwindow of opportunity. large a providing time, of period long a for blood the in remain agents pool blood stimulated muchinterest among radiologists. The advantages of Bloodpool agents, also known asintravascular agents, have AGENTS POOL BLOOD agent. contrast MR oral effective intraven an of use the involve typically studies These conditions. malignant and disease bowel inflammatory as such pathology isincreasingly being usedinstead of CT toevaluate bowel imaging MR broadened. have indications clinical the and grown, examinat MR abdominal of volume the sequences, hold introductionand widespread availability of high qualitybreath - the with However, organs. abdominal the to addition in tract gastrointestinal the of assessment careful a require often which (AIOD) by MRA by (AIOD) The trisodium, Medical Imaging), formerly knownas Vasovist structure chemical serum to bond chemical resulting in a prolonged half prolonged a in resulting space, fluid extracellular the into capillaries the of out diffusion long pooling time ous gadolinium chelate, but there is still a need for an for need a still is there but chelate, gadolinium ous

Bayer Healthcare, Inc.) ( agent used for imaging aortoil imaging for used agent

CT scanning is typically used for thes for used typically is scanning CT

is A is over standard MR contrast agents is that they they that is agents contrast MR standard over of Ablavar blavar

of Ablavar of albumin. When bound to to bound When albumin.

(gadofosveset trisodium, Lantheus Lantheus trisodium, (gadofosveset - life within the blood pool. This This pool. blood the within life

is large enough to prevent ready ready prevent to enough large is

Currently, the only FDA only the Currently,

is a result of of result a is 11 Figure iac occlusive disease disease occlusive iac ). a ® (

reversible reversible often requested requested often gadofosveset gadofosveset albumin, e indications, indications, e - | 13 ions has has ions approved approved

the the Page

NOT FOR DISTRIBUTION Nephrogenic Systemic Fibrosis Systemic Nephrogenic Systemic Fibrosis Nephrogenic administered and published in 2000. inpublished and A FDAthe guidelines that noted 0.003mMol/kg, virtually half the doseof most gadolinium contrast agents. contrast systemic fibrosis ( steady The primary use of use primary The using extracellular gadolinium chelates, arterialobtainedto phaseareimages chelates, extracellular gadolinium using an arterial phase image is phaseimage arterial an obtained. whichcanTypicallyimagesbe vascularprovideswindow much a broader during agents pool blooduseof blood imageacquisition.of pool The adequate shortening the during T1 ensure controf injection the imageacquisition ofrelative to The bed. timing arterial Although ra Although EVENTS ADVERSE POTENTIAL knees the stra However steady arterial phase imaging. The prolonged blood poolimaging.prolonged half The phase arterial longtoo are for imageacquisition times that imagesbe obtained using highcan resolution period, system can be acquired.canbe system venousandthehighofimages resolution injection, intravenous singleafter a territories vascular potential problem when using when problem potential ightforward, and overlap does not occur. However, in some vascular territories, eg, below vascularHowever, someterritories, inoccur. overlap not and ightforward, does - - state state (or equilibrium phase)equilibrium (or state

with Ablavar, a window of several hoursseveral follows a windowAblavar,of with , overlap c overlap, • • • re

images chelates. gadolinium , Spurious Spurious EventsAdverse Acute N GBCA administration can result in can result administration GBCA ephrogenic System ephrogenic Nephrogenicis fibrosis systemic NSF Ablavar . ould In most vascular beds vascular In most ) )

risk remains the atremains same the 0m risk H 21 be confusing. be

ypocalcemia

acquired inacquired

is is for for for (NSF) any

imaging glomerular filtration rate (GFR) rate filtration glomerular

The first case of NSF was recognized in California in 1997in wasNSFincaseofrecognized California first The

images of the vascular system can be acquired. Duringtimethis can be ofsystemimagesacquired. vascular the ic

blood pool agentpool blood

Fibrosis the same manner as samethe manner is is

a potentially serious adverse reaction to intotravenouslyadverse a reaction potentially serious

blood vessels. In contrastblood vessels. In , , the arterial and venous anatomy is relativelyvenousanatomyis and arterial the

discussed three types of adverse events:adverse of types three l /min/1.73m

- is t is life of of life - chelate contrast chelate he overlap of arteries and veinson and arteries heof overlap

contrast administration, during which during administration, contrast

with a with Ablavar later 2

to reduceto even in

nal gadolinium chelate. chelate. gadoliniumconventio nal

- this material this

enhancedMRA examinations also for low for

agents. agents. allows imaging of multiple multiple of imaging allows nephrogenic nephrogenic ast material is critical to to critical is material ast -

visualize concentration concentration

. It shouldbe It | 14

the target the Page

NOT FOR DISTRIBUTION Table * up to Oct Oct to up administration of administration haveNSFacquiredbeentohas everreported following kidneywithfunction normal patient No StageCKD.andinNSFnoted 4 of 3 havecasesbeen althoughanumber very small (CKD), 5Stage chronicdisease with kidney severe, exclusively almost patients reportedin is NSF dissue DrugFood and 2006, Administration the In in both Stage 5 CKD patients andpatients. NSF5 Stage CKD patients both in easily because not discernible is NSFof victims of preciserate determininga mortality CKD withsignificant, 5 Stage is patients and gadolinium exposur e. and gadolinium compared to the millions of patients that have patients that the to of millions compared NSF globally( agent agents, agents, involved and are believed to account for the account tofor believed are involvedand becomeswheelchair patient agents. gadolinium of administration following NSF havetoacquired reported haseverbeen function normal kidney patient No with 5 Eovist® Ablavar® MultiHance® Prohance® Gadavist™ OptiMARK Magnevist® Omniscan™ . R the incidence of incidence the 2010 vs Feb 2009 for the others the for 2009 Feb vs 2010 eported cases of NSF per GBCA dose in millions. in dose GBCA per NSF of cases eported

Agent

™ -

based contrast based

a

gadolinium Table NSF is is NSF 22 5

- As As ) bound. Internal organs such as the liver, heart, and lungs heart,often areliver,and suchas the organsInternal bound. . - While the number of cases is largeenoughjustiftois numbercases of the While based contrast agent. based contrast of February2009,of extremely a cardiovascular event

Reported Cases patient extremely painful be the to nature thiscan of Induration later by later extremities followed distal the of swelling symptoms Typical Symptoms ly follows to the to ly follows common disability

rare. significa 135 438 # 0 0 0 1 2 7 safely safely

andcause

induration

25

there have been 584reportedhavebeen cases there a warning regarding the link betweenthewarning regardingNSF a link 24 nt received gadolinium received

Because the mortality rate among mortalityBecause therate mortality rate of NSF patients.

is typically typically is

significant loss of skin flexibility. Acute Acute lossskin offlexibility. significant of of the skin the of

NSF begin with mild to moderateNSFto withmild begin the primary cause of deathcauseof primary the ( Figures Doses Given Doses (in millions) (in -

point where point based contrast contrast based 0.15 0.05 12.3 6.0* 6.0 0.8 95 47

12-14 several weeks weeks several y action, when action,

23 ). | 15 the the

of single of

Page

-

NOT FOR DISTRIBUTION chelates onmarket.the chelates

at after the administration of GBCAs after administration the believedat doesoccur? NSFIt is th Why frequently of manufacturers severalthereare earlier, described As Epidemiology transplantation appears to be a factor in patientsina appears be with to factor transplantation dialysis oftiming treatment, age, Neither withgender, race, NSF. associated CKDhasbeen other otherthan patient factor no note is that important to it Again, Omniscan are believed to bind their believed to to are with interacts e hours,gadolinium 24 approximatelyfre soft accumulatestissues. the inWithin gadolinium separated, chelate.free itsOnce be can separated from become CKD, gadolinium bundles. There is noNSF.laboratoryis for test There bundles. andcollagensofttissues in gadoliniumskin the andbiopsyindicating deep exposure, of thus leading to the observable manifestations of nephrogenicofobservable leading the to manifestations thus the the diagnosis of NSF comes from observation of clinical symptoms, history of gadolinium gadolinium historyof clinicalsymptoms,NSF of diagnosis observation of comes from

used in the U thein used accounts accounts majority for the monocytes

.S. Magnevist

and macrophages and are cognate receptors cognate

(

therefore ionic ofNSF cases. ) and

to produce to 28

most often associated with NSF. Of the two, the with NSF. oftenOf associated most

Omniscan Omniscan ( to stimulate the overproduction of collagen of overproduction the stimulate to 26

S tage 5 CKD CKD 5 tage profibrotic profibrotic FDA nonionic - systemic fibrosis.Conf approved gadolinium . The cytokines cytokines cytokines The . ) ) whodevelop are by far the by aremost the far click here. here. click information, more For NSF with patient a of calf upper and knee, thigh, indur and appearance peel” “orange of the skin typical of NSF. NSF. of typical skin the of demonstrates Medicine News Medicine Figure here. click Information, more For arm upper the of back the on plaque Figure

to r renal renal nor

patients with patients 13 12 NSF. ation of the the of ation . . -

- Uremic Uremic Frost Internal Internal of a patient patient a of roaming (Right) Typical Typical (Right) (Left) (Left) based based i rmation

| 16 induration induration 27

Sclerotic Sclerotic , , Page

NOT FOR DISTRIBUTION noare There known Treatment and IV sodium thiosulfate. While each of these thiosulfate. sodium IV and While Other corticosteroids. spontaneousofrecover cases considered an effective NSF treatment protocol. There aneffective treatment NSF considered s sample Year Table 6. 6. Table 1988 2008 2007 2006 2005 2004 2003 2000 1999 1997 1993 1992 1991

of NSF patients, none has shown enough of a statisticallynonea ofhas patients,shownNSF ofenough MR Contrast Agent and Nephrogenic Systemic Fibrosis Timeline Fibrosis Systemic Nephrogenic and Agent Contrast MR

that kidney patients will develop NSF” develop will patients kidney that likely more it making thereby recipients, of bodies the within free will become gadolinium make chemical “[T]he that alleging lawsuit First NSF for proposed “trigger” Gadolinium (MultiHance) dimeglumine gadobenate for approval FDA NSF with patients 15 of report First identified NSF of case First ) (ProHance gadoteridol for approval FDA technologists radiologic of practice of scope the within is media contrast of administration that proposes ASRT (Magnevist dimeglumine gadopentetate for approval FDA Event FDA calls for “boxed warning” for gadolinium for warning” “boxed for calls FDA media contrast injectable for agreement sign Novation and Healthcare GE Nycomed/Amersham purchases Healthcare GE FDA ) (Omniscan gadodiamide for approval FDA approval for gadoversetamide ( gadoversetamide for approval

accepted attempted treatment methods have included oral thalidomide, pentoxifylline, oral havethalidomide, included treatment attempted methods

y effective treatment and positive effect positive and

OptiMARK

attempts s s for NSF.However for from attempted attempted from - based contrast agents contrast based - ) ) is

American Journal of Roentgenology of Journal American here. click information, more For NSF. with consistent (arrows) muscles skeletal inthe changes inflammatory and edema and heads) (arrow thickening dermal demonstrates thighs right and left the of suppression Figure 1 up of Omniscan makes it more likely that that likely it more makes Omniscan of up

has demonstrated has

noprophylactic 4

) ) . Axial T2W image with fat fat with image T2W Axial . significant significant treatment 31 , ,

there have been reported havebeen there

treatment

positive results in smallin results positive

benefit to be benefit to with

oral and topical oral

for NSF for | 17

Page . 29

NOT FOR DISTRIBUTION

reactions and be able to manage each type of adverse event. adverse of type each manage to able be and reactions serious more and effects side mild between differentiate to prepared be staff technical MRI the that is “reaction” A dosage. correct with ( intervention medical - non are which effects, side mild very a While administration. gadolinium of risk only the not is fibrosis systemic nephrogenic Developing Events Adverse Acute NSF.documentedcaseof and approvalfirst c gadolinium lower some gadolinium NSF, haveNSFofcases been reported at readministration. for elimination of elimination for time of period sufficient a allow and dose recommended nephrogenic systemic nephrogenic gadolinium laboratory and/or history a obtaining by dysfunction renal for patients all Screen organs. internal and muscle or fatal in result may NSF (MRI). imaging resonance magnetic non- with available not and essential the unless agents contrast gadolinium of use avoid patients, these In Gadolinium W - risk risk arning • • patients priorIV to patients gadolinium

debilitating systemic fibrosis affecting the skin, skin, the affecting fibrosis systemic debilitating - hepato the to due any severity of insufficiency renal acute rate filtration (glomerular insufficiency renal severe chronic or acute perioperative liver transplantation period. transplantation liver perioperative

: N : - - based contrast agent, do not exceed not do agent, contrast based based contrast agents increase the risk for for risk the increase agents contrast based ephrogenic

the agent from the body prior to any any to prior body the from agent the renal syndrome or in the in the or syndrome renal , asearlierdiscussed oncentration,

Table 7 Table fibrosis (NSF) in patients with: patients in (NSF) fibrosis lso rare, acute adverse events can occur. These adverse events range from from range events adverse These occur. can events adverse acute rare, lso

-

tests. When administering a administering When tests. based IV contrast manufacturers have developed IV contrasts withhavedeveloped contrasts IV basedcontrast IVmanufacturers diagnostic information is is information diagnostic S

F ystemic ). A “side effect” is is effect” “side A ). <30m contrast unintended and harmful and unintended virtually zero. In addition to identifying patients at for risk patients identifyingto addition In zero. virtually allergic events, to more serious allergic reactions that require require that reactions allergic serious more to events, allergic l /min/1.73m se Sincese the administration. ibrosis - based based

enhanced enhanced

the the

predictable 2 )

or

. Table 6 Table , even with correct dosage. It is important important is It dosage. correct with even , and can be desirable or undesirable even even undesirable or desirable be can and procedures to measure the GFRtheto measure procedures follow MR all facilities Today, separat is NSFofthe onset the for the CKD and mechanism severe patients with affect to known is NSF Since NSF. for risk at patients those identify to guidelines agencies health with other government global along DrugAdministration, and Food onsetof prevent the NSF, To Prevention distinguish chelate, contrast agents. contrast warning box issuedFDAa black the 2007, health. measured kidney

shows the timeline of GBCA showstimelineofthe guidelines ion

on all on g it is logical to identifyand to logical is it

ofits gadolinium from thos - based contrast agent agent contrast based e patients based on based e patients ,h adolinium 30

were, issued the

asprovided Thus, in Thus, - based | 18 the the

Page in

NOT FOR DISTRIBUTION made available on a quarterly basis for public review.public basis for available a quarterly on made into an Adverse Event Reporting System (AERS), also known as MedWatch. also MedWatch. The knownSystem as Adverse(AERS), Reporting an Event into administration associated be reported withevents gadolinium adverseall requires FDAthat The monitoring patient equipment used so for that imaging the room of immediatelyoutare transported patients haveand on- effects adverse MRIiodinatedofcontrast.technical administration from Moderate *** ** * Shaking Anxiety Chills Dizziness *** face eyes, of Flushing/swelling *** Headache stuffiness Nasal the of (paling Pallor Warmth hives Rash, ** Itching *** Cough Sweats A N Table 7. Table

* * taste ltered * * vomiting ausea, reaction

si s *** de effect or reaction effect ide *** *** *** ***

ACR Categories of Reactions to GBCAs. to Reactions of Categories ACR ***

to **

and treatment

Mild SideMild Effects/

severe acute adverse reactions to GBCAs are similar to reactionsexperiencedtosimilar GBCAsreactions are to severeadverse acute

** Reactions

skin)

***

do not do

site equipment and medications availableand equipment siteand medications

become magnetic magnetic become Mild hypotension Mild Bronchospasm Dyspnea erythema Generalized Hypertension Tachycardia/bradycardia  edema Laryngeal

not listed but presumed 32

Reactions

Moderate

missile 34 or diffuse diffuse or

, wheezing , staff must be trained in recognizing recognizing inbe trained must staff

, endangering the patient and staff. patient endangeringthes,

ulmonary arrest ulmonary Cardiop Death arrhythmias Clinically hypotension Profound progressing) rapidly or (severe Convulsions edema Laryngeal

Unresponsiveness

 ready. ready. Typically,

Reactions Severe manifest manifest

reports

| 19

Page are are

33

NOT FOR DISTRIBUTION risk factors administration, gadoliniumnegativeto a patientsreaction experiencing prevent from To Risk f Risk anaphylactoid, anaphylaxis, or hypersensitivity or anaphylaxis, anaphylactoid, weredueallergic, todeathsall ifnot Most GBCAone administrations. inmillion than 2004FDA - from the repordeathstoadministration attributable40 GBCA ofwerea total NSF, there Excluding gadodiamide (Omniscan) and gadoversetamide ( and (Omniscan) gadoversetamide gadodiamide approvedUnitedcontrasttheStates agents in extracellular gadolinium theof Two Hypocalcemia Spurious in laboratory serum calcium measurements serumcalcium measurements laboratory in The American College of Radiology offers these contrast reaction treatment guidelines contrast reaction these RadiologyoffersCollege ofAmerican The ACRGuidelines ecially ecially esp life be While administration. administration. not the result of true true reduction of result the not healthcare costs. healthcare andincreased inappropriate treatment, in errorsincluding diagnosis, provider, healthcare bothand adverse offor patient outcomes a number risk the increase for mayreadings assay colorimetric • • • • • • • •

- actors GBCAs are GBCAs threatening. History of asthma,beyond seasonal of History GBCAto reaction Previous Rapid recognition, assessment, anddiagnosis assessment, recognition, Rapid life support life advanced and/or cardiac cardiopulmonary capablepersonnelresuscitation of Competent Tenuous health; may not survivehealth; notanaphylacticmay Tenuous contrast iodinated reactionstoagents allergic Previous aspirin particularlyallergies, to of History gen, IV, continuous monitoring, epinephrine at a concentration of 0.3of a mgconcentration epinephrine at continuous monitoring, IV, gen, Oxy to should be considered prior to the scanconsidered be prior the should to :

at - T risk patients. risk he reductions in reported serum calcium levels are artifactual serumlevels are in calcium he reported reductions

extraordinarily safe and most acute reactions are mild, severe reactions can can severe mild,arereactions acute reactions and most extraordinarilysafe

is used to measure serum calcium postcontrast administration. Such administration. false calciumpostcontrast measure usedserum tois MR 2009. While unforeseen and tragic, unforeseenandt tragic, 2009. While I personnel must remain vigilant when administering gadolinium, when vigilant administering gadolinium, remain must personnel

38

in

calcium le calcium vel over

s - type reactions type in the body but of false values reported whenvaluesofa false reported bodybut the in

the 24- the OptiMARK 36

shock hour period after contrast contrast periodafterhour his translates to a death rate of less aless of rate to hisdeath translates ) — )

. 35

can cause temporary reductions canreductions causetemporary , that is, is, that , — | 20 they arethey 37 these : : ted to to ted Page

NOT FOR DISTRIBUTION MR diagnostic imag effectivesafe and a remains NSF.administrationof Gadolinium cases safely beto used GBCAs withcontinue pathologyMRI. of agentsconspicuity enhancesthe contrast disea abnormalofand conditions most diagnosis the in modality imaging critical a remains MRI SUMMARY contrastadministration. of hourswithin 24 blood laboratory undergo tests they calciumlevels if serum artificially altered for serumcalciumwithcolorimetric the interfere assay not contr aafter hours 24 withindetected patientswithareinhypocalcemia repeated measurements such such lowered measurements lowered duecalciumto intravenouslycalcium orfalsely with oral supplements administered treated interventions. threatening perhapsunnecessaryand evenliwith with lowcalciumand treated serum diagnosed associatedwith main risk The normocalcemia. normocalcemia. andhypocalcemiaspurious associated riskswith spurious minimizecanto be taken the Steps adequatelyor followed. identified been havenot risk patientsatof hypocalcemia unknownspurious majority isbecause the to ast risk , and since the implementation of FDA guidelines in 2007, there have been noreportedhavebeen FDA there ofsinceimplementation 2007, theguidelinesin and , - enhanced MR examination. The simplest solution is to use a contrast agent that doesagentuse a that contrast is to simplest solution enhancedMR The examination. . Some clinical laboratories have implemented a policy whereby serum calcium calcium apolicy have implemented serum whereby Some clinicallaboratories

Increasing the awareness of the problem through education obviouslyeducationr the ofthrough awareness theproblem Increasing ing .

of serumcalcium. of

T here have been several documented cases of patients incorrectly ofcases patients haveherebeen documented several

spurious spurious

hypocalcemia is that a patienterroneouslyhypocalcemiacoulda be is that 39

The actual prevalence of inappropriate therapydue inappropriateof prevalence The actual characterization of normaland tissuethe characterizationof se states.

or to inform the patient of the potentialof patient the inform the to or The use of gadoliniumuse The adjunct to to adjunct high - based based fe - | 21 quality - s educe Page

NOT FOR DISTRIBUTION 8. systemic fibrosis. Directors. Fellowship Neuroradiology of Society American Accessed April 27, 2012. 27, April Accessed at: Available Drugs. Approved FDA 18. Insert. Package Eovist® 17. ing:Model http://pharmaceuticals.covidien.com/Pharmaceuticals/pageBuilder.aspx?topicID=132292&page=Imag 16. http://www.gehealthcare.com/caen/md/docs/omniscan.pdf at: Available Insert. Package Omniscan™ 15. at: Available Med. Daily 14. 142882.htm http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm Gadolinium on Information FDA 13. 2012. 26, April Accessed http://www.acr.org/SecondaryMainMenuCategories/quality_safety/contrast_manual/FullManual.aspx at: Available 2010. 7, Volume Media, Contrast on Manual Radiology of College American 12. Self patient: 11. lactation. and pregnancy (ESUR) Radiology Urogenital of Society 10. Physician. 9 and women Shellock 7. gadolinium to reactions adverse of Occurrence JH. Ellis B, Mermillod RH, Cohan KT, Szopinski KP, Murphy 6. cases. 36 RH. Cohan JA, Brunberg KJ, Murphy 5. - 2001;176(6):1385 Jun 4. 2012. 27, April Accessed at: Available Insert. Package Eovist® 3. 27, April at: Available Insert. Package Magnevist® 2. dCentralNervousSystemDrugsAdvisoryCommittee/UCM241072.pdf http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/Peripheralan at: Available Gadolinium FDA 1. REFERENCES . Garcia

Sundgren PC Sundgren Cochran ST. Trends in Adverse Events After I After Events Adverse in Trends ST. Cochran

Webb JA Webb OptiMARK I Lee , Chew FS 2012. - . A Bournissen F Bournissen AJR.

- 2006;52:309 - FG, Spinazzi A. MRI safety update 2008:part 1. MRI contrast agents and nephrogenic nephrogenic and agents contrast MRI 1. 2008:part update safety MRI A. Spinazzi FG, based contrast material and management of patients at increased risk: a survey of the the of survey a risk: increased at patients of management and material contrast based - . Accessed April 27, 2012. 27, April Accessed . children small ccessed April 27, 2012. 27, April ccessed . module assessment Thomsen HS , Thomsen ™ Package Insert. Available at: at: Available Insert. Package ™

- Oct;167(4):847 1996 ,

Leander P Leander AJR; AJR; - Use of of . Use Based Contrast Agents (GBCAs) and the NSF Risk: Regulatory Update 2011. 2011. Update Regulatory Risk: NSF the and (GBCAs) Agents Contrast Based 1388. , – 2008;191:1129 310. Shrim A Shrim

Eur Radiol Eur

justified Morcos SK , Morcos . Is administration . Is IV

http://dailymed.nlm.nih.gov/dailymed/drugInfo

iodinated Koren G , Koren AJR Am J Roentgenol J Am AJR ? - .

Based Contrast Agents. Available at: at: Available Agents. Contrast Based J Magn Reson Imaging. Magn Reson J

- 2005;15(6):1234 849.

http://www.fdaapproveddrugs.us/lumenhance.html ; 1139. . The use of iodinated and gadolinium contrast media during during media contrast gadolinium and iodinated of use The . Adverse http://bayerimaging.com/products/eovist/characteristics.php and and Members of Contrast Media Safety Committee of European European of Committee Safety Media Contrast of Members

. Safety of gadolinium during pregnancy. pregnancy. during gadolinium of Safety . http://bayerimaging.com/products/magnevist/ gadolinium

of of V Administration of Contrast Media Cases. Cases. Media Contrast of Administration V gadolinium reactions to gadolinium contrast media: a review of of review a media: contrast gadolinium to reactions 1240.

. contrast media in the pregnant or lactating lactating or pregnant in the media contrast

- Suppl):S70 2009;193(6 . Accessed April 27, 2012. 27, April Accessed . Acad Radiol. Acad -

contrast based - 2011;34(4):750 . Accessed April 27, 2012. 27, April Accessed .

- Nov;6(11):656 1999 . Accessed April 27, 2012. 27, April Accessed .

to pregnant to media 757.

73. Can Fa Can

. . Accessed . m AJR 664.

| 22

;

Page .

.

NOT FOR DISTRIBUTION cases of nephrogenic fibrosing dermopathy and review of the literature. literature. the of review and dermopathy fibrosing nephrogenic of cases Radiology Gadodiamide al. et RW Lent HE, Erel MR, nce Pri 39. 2011. Prince, 34. . 2010 7, Volume Media, Contrast on Manual Radiology of College American 37. 36. 35. MedWatch. 34. Ibid 33. reactions. media MR, Prince 32. 2008. PM, Colletti 31. 25. 24. 2006 23. Gadolinium FDA 22. http://www.amagpharma.com/documents/products/pdfs/GastroMARK_insert.pdf at: Available website. Medical Lantheus 21. GastroMARK 20. 2012. 27, April Accessed Available website. FDA 19. 27. 26. January Companies. Hill Radiol Eur http://www.amagpharma.com/documents/products/pdfs/GastroMARK_insert.pdf http://www.fda.gov/Safety/MedWatch at: Available Program. Reporting Event Adverse and Safety FDA The MedWatch: 30. 29. 2010. J, Kay 28. Roentgenol

Mend . . gadodiamide to reaction adverse late serious a fibrosis: systemic Nephrogenic HS. Thomsen Colletti PM. Nephrogenic Systemic Fibrosis and Gadolinium: A Perfect Storm A Perfect Gadolinium: and Fibrosis Systemic Nephrogenic PM. Colletti . . 2011 MR, Prince Prince Fibrosis. Systemic Nephrogenic J. Kay Kay J, 2010. J, Kay Kay J, 2010. J, Kay ; -2 Feb;35(4):238

oza FA, Arlett CM, Sandorfi N, Latinis K, Latinis N, Sandorfi CM, Arlett FA, oza .

.

MR - 2003;277:639 . 2008; . ;16 2006 , 2011. ,

Zhang H, Zou Z, Staron RB, Brill PW. Incidence of immediate gadolinium contrast contrast gadolinium immediate of Incidence PW. Brill RB, Staron Z, Zou H, Zhang The FDA Safety and Adverse Event Report System. Report Event Adverse and Safety FDA The

® Package Insert. Available at: at: Available Insert. Package ®

AJR Am J Roentgenol . Roentgenol Am J AJR - 191:1150 (12) - Based Contrast Agents (GBCAs) and the NSF Risk: Regulatory Update 2011. Update Regulatory Risk: NSF the and (GBCAs) Agents Contrast Based

49. :2619

15 . . 646 at: . . , 2010 1153. – http://www.fdazilla.com/fda/drugs/application/020292 2621.

. Accessed April 27, 2012 27, April Accessed . - 2011;96:W138 A ccessMedicine from McGraw from ccessMedicine Piera dministration administration - Velazquez 143.

. .

S, Jimenez SA. SA. Jimenez S,

c auses of of auses . Rheum Arthritis Semin - Hill © 2010 The McGraw The 2010 © Hill h . Accessed April 27, 2012. 27, April Accessed . 2012. 27, April .Accessed ypocalcemia. ypocalcemia. . AJR Description of 12 of Description . .

Am J J Am | 23

Page

-

NOT FOR DISTRIBUTION intracellular comparedcelltothe as outside literally, extracellular cells neighboring to signalscarry that bysecretedcells, proteins, various anyof cytokine safe agentseffectivemaketo them contrast synthesisof usedin gadolinium the atom; central singleand liganda bonded multiple bondsbetweena coordinate separate the chelate GLOSSARY

atom metal a central binds to molecule orthat ion an ligand surrounding spinalthe cord) space (intrathecal canal spinalinto the injection an intrathecal/intrathecally skin the of thickening or hardening induration molecule atom orcharged positively negatively a or ion/ionic contrastagents. CT elementin widelyused most it the makes atomic weight high 53. of Its weight atomic withan element chemical nonmetallic a contrast/iodine iodinated liver’smass of the 80% 70 comprises cell that liver’s typemain the hepatocyte irritate extravasation aconcern,notsafety While tissues. soft surrounding the vesselinto leaksof out contrast the material the of occurs when extravasation some contrast, gadolinium IV giving In tissues. surrounding vesselinto a of fluids from escape extravasation formation or presence of two or ortwoof presence formation s the tissues and can be painful.and canbe s tissues the

or inside theinside or cell

more

and - calcium level calcium hypocalcemia ,depressedspurious a falsely usedinauthentic;or as genuine not spurious values. aslowerto compared tissue the from signal inter brigh resulting relaxivity,the greater value, the numeric higher the The material. contrast the proximityin close to come tissues causein that to relaxation GBCA T1 a numerically,of expressed ability, the relaxivity compound compound of a measure water; of or water milliosmoles kilogram per of per osmoles of unitskilogram in measured osmolality is butneutral positivelycharged negatively neither nor is atom that an nonionic ion metal aaroundchemically atoms binds that classofchelates GBCA structural a agent contrast macrocyclic chain withstructure a ions gadolinium binds that classofchelates GBCA structural a agent contrast linear magnetic magnetic external the which amplifies gadolinium, eg, not yet ferrous, magnetic field a toslightly thatis element attracted an paramagnetic equalize twosolutions of is concentrations the that the result net thedissolvedof substance; concentration higherofarea dissolved an substance to of loweranofconcentration area from water, solventsuchas of molecules, diffusion the osmosis solution of liter per milliosmoles orosmoles of units in measured osmolarity

field produced by the MRIproducedsystem by the field

to cause osmosis cause to

the the

ability ability

of achemical of

- bound | 24 Page

NOT FOR DISTRIBUTION NSF MRA HCC GFR GBCA FNH r mOsm/kg Osm/kg T2* r FDA CKD AIOD AERS ACR TERMS OF ABBREVIATIONS 2 1

hepatocellular carcinoma hepatocellular DrugAdministration and Food glomerular filtration rate filtration glomerular gadolinium nodularhyperplasia focal nephrogenic systemic fibrosis nephrogenic angiogram/angiography resonance magnetic milliosmoles per kilogram of water of kilogram per milliosmoles waterof osmoles/kilogram T2 star T2 relaxivity T2 relaxivity T1 chronic kidney disease kidney chronic Adverse CollegeRadiologyof American aortoiliac occlusive disease aortoiliac

Event Reporting System ReportingEvent - based contrast agent contrast based

| 25 Page