Guideline on the use of Gadolinium-containing MRI Contrast Agents in Patients with Renal Impairment

The Royal Australian and New Zealand College of Radiologists® Guideline on the use of Gadolinium-containing MRI Contrast Agents in Patients with Renal Impairment

Clinical Radiology

Guideline

Name of document and version: Guideline on the use of Gadolinium-containing MRI Contrast Agents in Patients with Renal Impairment, Version 3

Approved by: Faculty of Clinical Radiology Council

Date of approval: 21 November 2019

ABN 37 000 029 863 Copyright for this publication rests with The Royal Australian and New Zealand College of Radiologists ®

The Royal Australian and New Zealand College of Radiologists Level 9, 51 Druitt Street Sydney NSW 2000 Australia

New Zealand Office: Floor 6, 142 Lambton Quay, Wellington 6011, New Zealand

Email: [email protected] Website: www.ranzcr.com Telephone: +61 2 9268 9777

Disclaimer: The information provided in this document is of a general nature only and is not intended as a substitute for medical or legal advice. It is designed to support, not replace, the relationship that exists between a patient and his/her doctor. TABLE OF CONTENTS

1. Introduction 4 2. Nephrogenic Systemic Fibrosis 4 3. Recommendations 7 4. Further Information 10 5. Related documents 10 6. Acknowledgements 10 7. Appendices 10 8. References and Bibiolography 10

Page 2 of 14 About the College

The Royal Australian and New Zealand College of Radiologists (RANZCR) is a not-for-profit association of members who deliver skills, knowledge, insight, time and commit to promoting the science and practice of the medical specialties of clinical radiology (diagnostic and interventional) and radiation oncology in Australia and New Zealand.

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The Code defines the values and principles that underpin the best practice of clinical radiology and radiation oncology and makes explicit the standards of ethical conduct the College expects of its members. Guideline on the use of Gadolinium-Containing MRI Contrast Agen

Page 3 of 14 Guideline on the use of Gadolinium-Containing MRI Contrast Agen da Version 3 | © The Royal Australian and New Z ealand College Radiologists® November 2019 1. INTRODUCTION

1.1 Purpose and scope

(a) The Guideline on the use of Gadolinium-containing MRI Contrast agents in patients with Renal Impairment has been developed by the College’s Safety, Quality and Standards Committee’s MRI Reference Group. It is designed to provide guidance to radiologists on the safe and effective use of contrast agents used to enhance Magnetic Resonance Imaging examinations.

(b) This guideline is a consensus based document and provides information on nephrogenic systemic fibrosis (NSF) and risk to patients when administering contrast agents. It also provides recommendations on screening protocol and risk mitigation strategies to provide the safest environment for patients during diagnostic imaging examinations, whilst still ensuring appropriate access to imaging when clinically indicated.

1.2 Definitions

In this guideline:

AKI means Acute Kidney Injury

College means The Royal Australian and New Zealand College of Radiologists.

Member means a member of the College.

NSF means Nephrogenic systemic fibrosis

2. NEPHROGENIC SYSTEMIC FIBROSIS

2.1 What is NSF

Nephrogenic systemic fibrosis (NSF) is a relatively uncommon condition in which fibrous plaques develop in the dermis and, often, in deeper connective tissues. Reported cases have occurred almost exclusively in patients with severe renal disease, and almost all have been associated with prior use of gadolinium-containing MRI contrast agents. The disease is often disabling, no proven treatments exist, and it may contribute to patient death.

2.2 Who is at risk

Whilst cases have occurred in patients with either acute or chronic renal failure. most have been in patients with chronic and severe kidney disease (CKD Stage 4 & 5, glomerular filtration rate (GFR) < 30 ml/ min/1.73 m2); most have been on dialysis. In Stage 5 CKD, a single exposure to gadodiamide (Omniscan) carries a risk in the order of 1 % of subsequent NSF - with gadopentetate [Magnevist], the risk has been estimated at 0.1 - 1 %. Two cases initially reported as having had “moderate” renal failure (nominally Stage 3 CKD, creatinine clearance 30 – 60 ml/min/1.73 m2) are now acknowledged as having had acutely deteriorating renal function at the time. Only a very small number of cases of NSF have been reported in patients with stable eGFR > 30ml/min/1.73 m2 and in all these cases the eGFR was close to 30ml/min/1.73 m2. Thus it is likely that there is no absolute threshold GFR for risk but rather a continuum with substantially lower risk at higher GFR.

Page 4 of 14 Children under one year of age have a physiologically low GFR, yet no case of NSF has been reported in a patient under the age of 6 years. While it appears likely that additional factors other than a low GFR alone contribute to NSF, it is still considered by some as prudent to treat children less than 1 year of age and pregnant patients as also being at increased risk. In the past, some recommended caution in lactating patients because of the hypothetical risk of gadolinium excretion into breast milk; however it has been shown that, for at least some gadolinium-based agents, the proportion entering the breast milk is very small (in the order of 1% of the injected dose), and very little of this is actually absorbed. Hence the risk to the child would appear negligible.

Patients with co-existing severe liver disease and renal impairment, and renal impairment of any severity in patients within one month of liver transplant (before or after), are also regarded as being at increased risk. Chronic liver disease by itself does not appear to carry any increase in risk.

2.3 Clinical features & evolution

Onset typically occurs within days (occasionally hours) of gadolinium-based contrast injection, with pain, itch, swelling, and erythema in the affected part – most often a dependent region, particularly the lower limbs. Definitive diagnosis requires lesion biopsy – clinical features are mimicked by conditions such as scleromyxoedema. The lesions evolve into fibrous plaques in the dermis and subcutaneous tissues; plaques have also been reported in muscle (incl. diaphragm), heart, liver, and lung. Plaques in the limbs can cause crippling contractures.

A small number of cases appear to have a rapidly progressive course, but the disease contributes to death in a substantial proportion of cases.

2.4 Treatment

The best responses have been seen in patients whose renal function has been substantially © The Royal Australian Zealand and New College of Radiologists® | November 2019 improved, e.g. by transplant. Many other treatments are being tried, so far without a clear-cut preferred treatment emerging.

2.5 Are there any Australian cases? da Version 3 | There are reported cases in both Australia and New Zealand1. Cases should be reported to the Therapeutic Goods Administration (see http://www.tga.gov.au/safety/problem.htm), and to the manufacturer of any potentially implicated contrast agent.

2.6 Which agents have been implicated?

Cases reported in the peer-reviewed literature have been associated most often with exposure to gadodiamide (Omniscan), followed by gadopentetate (Magnevist) and gadoversetamide (Optimark).

Small numbers of cases, often unconfirmed, have been reported in patients who have received gadobenate (MultiHance), gadobutrol (Gadovist) gadoterate (Dotarem), or gadoteridol (ProHance), though almost all of these have been confounded by the fact that the same patients also received one or more doses of other agents more often associated with NSF. At the time of writing, no confirmed cases of NSF had been established after unconfounded exposure to gadobenate (MultiHance) or gadoterate (Dotarem). Recent publications have reported no cases of NSF in substantial cohorts of patients with chronic renal disease and/or dialysis treatment, who have intentionally been given macrocyclic agents or gadobenate.

Guideline on the use of Gadolinium-Containing MRI Contrast Agen The possibility that each of these 4 agents could be associated with the development of NSF has not been entirely excluded, though it seems on the available evidence that any such association would be extremely rare. Experience with gadoxetate (Primovist) remains limited.

Page 5 of 14 2.7 What us the pathogenesis? Guideline on the use of Gadolinium-Containing MRI Contrast Agen da Version 3 | © The Royal Australian and New Z ealand College Radiologists® November 2019 A bone-marrow-derived fibrocyte seems to be central to the pathobiology of the condition. It is not known what triggers its abnormal behaviour, however two lines of evidence have been presented that implicated loss of gadolinium from the chelating agent:

(i) Animal studies have shown that biological clearance of gadolinium after injection of less stable chelates is much slower than after injection of more stable (cyclic) chelates; (ii) Chemical analysis of NSF plaques in clinical cases has found relatively high levels of inorganic (i.e. de-chelated and subsequently metabolised) gadolinium.

It is emphasised that, while suggestive, these observations do not prove a mechanism involving de-chelation and/or transmetallation to be the pathway to NSF. Experiments in cell culture have shown that gadolinium chelates can stimulate fibroblast proliferation and enzyme activation, with the agents more commonly implicated in NSF showing these effects at much lower concentration thresholds. The precise mechanism of these effects has not yet been established.

2.8 Which chelates are more “stable”?

Chelate stability is reported in several ways, reflecting different parameters affecting the equilibrium between gadolinium ions, their ligands, and chelated ions; some are more relevant to laboratory conditions, others attempt to reflect biological conditions. In general, chelates with a cyclic structure (gadoterate, gadoteridol, gadobutrol) are more stable than linear molecules such as gadobenate, gadodiamide, gadopentetate, and gadoversetamide. Gadodiamide and gadoversetamide are less stable chelates than the other linear agents. This ranking has recently been confirmed in studies in human serum at physiological temperatures and pH. It should be noted, however, that although gadobenate (MultiHance) has a similar stability profile to the other linear chelates, clinical data suggest that it is nevertheless associated with a very low risk of NSF.

2.9 Gadolinium retention

Recently it has been recognised that small amounts of gadolinium are retained in the body for significant periods, possibly indefinitely, after intravenous injection.

This has been best documented in the brain (particularly the cerebellar dentate nucleus and the globus pallidus), but is also known to occur in bone marrow and skin.

The extent of retention is greater for the less stable (linear) chelates of gadolinium.

Retention appears to be more extensive in patients with renal impairment, at least for the less stable (linear) chelates. Thus it may be prudent to prefer macrocyclic chelates, unless there is a clinical indication for the use of another agent.

At the time of this revision of the guidelines, no adverse effect of gadolinium retention has been identified.

As a result of this new information, the European Medicines Agency has removed the linear chelates gadodiamide and gadopentetate from the market, while gadoversetamide was withdrawn by the vendor. The US FDA and the Australian TGA have not moved to remove any agent from the market.

At this stage, it is not felt that this information warrants any change to the recommendations below.

Page 6 of 14 3. RECOMMENDATIONS

3.1 Risk Factors for Kidney Disease

All patients for whom the use of a linear gadolinium-based MRI contrast agent is being considered should be screened for the presence of kidney disease. Screening should include review of available medical records, as well as questioning of the patient (or relatives and acquaintances where the patient is unable to respond appropriately). Relevant indicators to be sought include:

 Previous laboratory tests (GFR, serum creatinine, eGFR)  Known history of kidney disease or dialysis  Known family history of renal disease  Age > 60 years  Aboriginal, Torres Strait Islander (ATSI), Maori or Pacific Islander ethnicity  History of diabetes  History of vascular disease – previous AMI or stroke  Hypertension  History of smoking  BMI > 30  Gout

If a macrocyclic agent, or gadobenate, is to be used, screening for renal disease is no longer considered appropriate or cost-effective, given the extremely low risk of NSF with these agents, and the cost and inconvenience associated with screening, but can still be performed at the discretion of the practice, or of the radiologist in charge of the patient.

Patients on dialysis should still be identified prior to intravenous administration of lower-risk agents. © The Royal Australian Zealand and New College of Radiologists® | November 2019 3.2 Formal Assessment of Kidney Function

If one or more of the above risk factors for kidney disease are present, the patient is to receive da Version 3 | a linear GBCA, and there is no recent (<3 months for stable outpatients; <7 days for stable inpatients) laboratory tests available, serum creatinine should be obtained and an eGFR estimated. Following estimation of eGFR, risk stratification should be performed as detailed in point 5.

3.3 eGFR Measurement Reliability

Situations where eGFR measurement is an unreliable marker of GFR include AKI (Acute Kidney Injury) (note that serum creatinine may not stabilize until 7-10 days after an acute insult), peri-operative liver transplant patients, patients with “hepato-renal syndrome”, and patients with chronic liver disease where eGFR may overestimate true GFR. These patients are at significant risk for NSF, but the size of this risk remains poorly quantified at this time.

3.4 Alternative Imaging Modality

Consider whether any other imaging modality– including non-contrast MRI, CT, or ultrasound– could provide the required diagnostic information at less risk. CT using iodinated contrast may be considered as an alternative, but also has risks including ionising radiation exposure, and, in patients with CKD, contrast nephropathy with potential permanent loss of residual renal function. Do not use MRI contrast agents for CT or conventional angiography in an attempt to

Guideline on the use of Gadolinium-Containing MRI Contrast Agen avoid nephrotoxicity. In patients with previous severe reaction to iodinated contrast, where repeat exposure to an iodinated agent with pre-medication is not considered acceptable, the use of a gadolinium-based agent still carries some risk of a severe reaction, as well as (a) possibly higher risks of nephrotoxicity at the large doses sufficient to provide effective CT contrast enhancement; (b) uncertain risks associated with possible gadolinium retention.

Page 7 of 14 No patient should be denied any imaging investigation that is critical to clinical management; that is, the risk of NSF must be weighed against the risk of diagnostic error from a study performed without gadolinium contrast. Guideline on the use of Gadolinium-Containing MRI Contrast Agen da Version 3 | © The Royal Australian and New Z ealand College Radiologists® November 2019

3.5 High Risk Patients

In high risk patients, i.e. those in groups 3.6.4-6 below, where the perceived benefit of an MRI scan outweighs the risks it is recommended that:

(a) The minimum adequate dose of gadolinium is used.

There is evidence for a dose-risk relationship. Restrict dose to 0.1 mmol/kg and avoid repeat scans.

(b) Consider immediate post-scan haemodialysis.

A single conventional haemodialysis session will remove 75% of the free Gadolinium - a 2nd treatment 93% and a 3rd treatment 98% of a dose.

If the patient has severe renal failure, but is not receiving haemodialysis, the possibility of commencing haemodialysis will need individual consideration. To date, it is not known whether early haemodialysis post-procedure reduces the risk of NSF.

(c) Use a contrast agent with the lowest theoretical risk.

Choices which may reduce the risk include:

(i) use of the theoretically most stable chelates (those with a cyclic molecular structure) (ii) use of agents with higher relaxivity, allowing smaller doses of gadolinium for the same T1 shortening effect.

3.6 Risk Stratification

Risk stratification is performed according to clinical assessment and reported eGFR.

3.6.1 Stage 1 and 2 CKD- GFR> 60 ml/min/1.73m2 + No recognized risk factors for kidney disease

There is currently no evidence of increased risk from any of the marketed agents. There is a potential risk in individuals without risk factors but with undiagnosed kidney disease. There is also a theoretical risk of accumulation of gadolinium from higher risk chelates that should be borne in mind.

3.6.2 Stage 3 CKD - GFR 30 – 60 ml/min/1.73 m2

At milder levels of renal impairment, the risk of NSF appears extremely small. There remains a theoretical possibility of late and/or cumulative effects from gadolinium- based agents, perhaps related to persistence of small amounts of de-chelated gadolinium in tissues. Caution with the use of less stable higher risk chelates - gadodiamide, gadoversetamide*, and gadopentetate – may be appropriate in this group, particularly in patients who are pregnant or lactating.

3.6.3 Stage 4 CKD – GFR 15-30 ml/min/1.73 m2

These patients are at low risk for NSF (in the order of 0.1% per dose after higher-risk agents).

Page 8 of 14 Higher risk chelates (gadodiamide, gadoversetamide*, gadopentetate) are contra-indicated in this group and other agents should only be used after careful consideration.

3.6.4 Stage 5 CKD - GFR< 15 ml/min/1.73 m2

These patients are at significant risk for NSF (in the order of 1% per dose after high-risk agents).

Higher risk chelates (gadodiamide, gadoversetamide,* gadopentetate) are contra-indicated in this group and other agents should only be used after careful consideration.

3.6.5 Haemodialysis:

These patients are at high risk for NSF (greater than 1 % per dose after higher-risk agents).

The risk of CT with iodinated contrast agents may well be less than that of a gadolinium- enhanced MRI examination. If a patient is anuric, there is no longer a risk of nephrotoxicity.

If the benefit of a contrast-enhanced MRI examination is felt to outweigh the risk, and CT cannot be effectively substituted, use the minimum necessary dose of, an agent with a low frequency of NSF cases.

The MRI examination should be scheduled immediately before a dialysis session, to maximise clearance of the agent, and the possibility of a second session within 24 hours, and perhaps a third additional session, should also be considered. To date, it is not known whether early haemodialysis reduces the risk of NSF.

Avoid intravenous iron therapy at time of scan, as iron theoretically may displace gadolinium from its chelating agent. © The Royal Australian Zealand and New College of Radiologists® | November 2019

3.6.6 Peritoneal dialysis

These patients are at the highest risk for NSF da Version 3 | Avoid all gadolinium-based MRI contrast agents in patients receiving peritoneal dialysis. Patients on peritoneal dialysis have both reduced clearance of the Gadolinium and increased volume of distribution; in one study, their measured risk of NSF was seven times higher than that of haemodialysis patients)1.

In a case report in a single anuric chronic peritoneal dialysis patient, 90 percent of 0.1 mmol/kg of gadodiamide was removed from the circulation in two days with a regimen of 10 to 15 exchanges per day of peritoneal dialysis2.

If haemodialysis cannot be performed, we suggest more frequent peritoneal dialysis cycles for at least 48 hours after exposure, with no periods with a dry abdomen3.

Where the potential benefit of a gadolinium-enhanced MRI examination is thought to outweigh the risk to a patient on peritoneal dialysis, a low-risk agent (macrocyclic or gadobenate) should be used.

3.6.7 Written report

For any contrast-enhanced MRI examination, the name of the agent used, and the dose, must

Guideline on the use of Gadolinium-Containing MRI Contrast Agen be recorded in the patient record and/or the report of the examination.

Page 9 of 14 3.6.8 Consent Guideline on the use of Gadolinium-Containing MRI Contrast Agen da Version 3 | © The Royal Australian and New Z ealand College Radiologists® November 2019 In patients who will receive a higher-risk gadolinium-based contrast agent for their MRI examination, but who are at risk for NSF as defined in 3.3 and 3.6.3-6, the risks and benefits of gadolinium injection, or its being withheld, should be explained and formal written consent to the chosen course of action should be documented.

3.6.9 Patient Questionnaires

Where patient questionnaires are used to screen for renal disease, consideration should be given to periodic audit of their sensitivity, e.g. by comparison to routine eGFR testing.

Gadoversetamide has been withdrawn from the Australian market.

4. FURTHER INFORMATION

 Kendrick-Jones JC, Voss DM, de Zoysa JR, Nephrogenic systemic fibrosis, in patients with end-stage kidney disease on dialysis, in the greater Auckland region, from 2000–2006. Nephrology 2011, 16(2): 243-48.  American College of Radiology : http://www.acr.org/Quality-Safety/Radiology-Safety/MR- SafetyACR Manual on contrast media. Version 10.3, 2018 https://www.acr.org/Clinical- Resources/Contrast-Manual  European Society of Urogenital radiology : http://www.esur.org/esur-guidelines/ Radiology : ESUR Guidelines on contrast agents, v10.0, 2018 http://www.esur-cm.org/index.php/en/  US Food & Drug Administration : http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProvi ders/ucm142882.htm

5. RELATED DOCUMENTS

 RANZCR Iodinated Contrast guideline, version 2.3 Sydney, RANZCR 2018 https://www.ranzcr.com/fellows/clinical-radiology/professional-documents/

6. ACKNOWLEDGEMENTS

Click and type: List any acknowledgements. Delete section if not required

7. APPENDICES

A. Risk Factors for CKD – Flowchart B. Gadolinium-based MR Contrast Agent: Nomenclature C. Chelate Properties

8. REFERENCES AND BIBIOLOGRAPHY

1 Kallen et al AJKD 51: 966-975 2008 2 Murashima et al Clin Neph 2008 69,5 368 3 UpTo Date 2019

 A Systematic Review of 639 Patients with Biopsy-confirmed Nephrogenic Systemic Fibrosis. Attari H1, Cao Y1, Elmholdt TR1, Zhao Y1, Prince MR1. Radiology. 2019 Jul 2:182916. doi: 10.1148/radiol.2019182916. [Epub ahead of print]  Gadolinium-Based MRI Contrast Agents Induce Mitochondrial Toxicity and Cell Death in Human Neurons, and Toxicity Increases With Reduced Kinetic Stability of the Agent. Bower DV, Richter JK, von Tengg-Kobligk H, Heverhagen JT, Runge VM. Invest Radiol. 2019 Aug;54(8):453-463. doi: 10.1097/RLI.0000000000000567.  Virtual elimination of Nephrogenic Systemic Fibrosis: A medical success story with a small asterisk.

Page 10 of 14 • Davenport MS Radiology 2019 Jul 2:191158. doi:10.1148/radiol.2019191158 [Epub ahead of print] • Gadolinium Retention in the Brain: An MRI Relaxometry Study of Linear and Macrocyclic Gadolinium-Based Contrast Agents in Multiple Sclerosis. Forslin Y, Martola J, Bergendal Å, Fredrikson S, Wiberg MK, Granberg T. AJNR Am J Neuroradiol. 2019 Jun 27. doi: 10.3174/ ajnr.A6112. [Epub ahead of print] • Acute Adverse Events Following Gadolinium-based Contrast Agent Administration: A Single- Center Retrospective Study of 281 945 Injections. McDonald JS, Hunt CH, Kolbe AB, Schmitz JJ, Hartman RP, Maddox DE, Kallmes DF, McDonald RJ. Radiology. 2019 Jul 2:182834. doi: 10.1148/radiol.2019182834. [Epub ahead of print] • Observational study on the incidence of nephrogenic systemic fibrosis in patients with renal impairment following gadoterate meglumine administration: the NSsaFe study. McWilliams RG, Frabizzio JV, De Backer AI, Grinberg A, Maes BD, Zobel BB, Gottschalk A. J Magn Reson Imaging. 2019 Jul 9. doi: 10.1002/jmri.26851. [Epub ahead of print] • Cumulative gadodiamide administration leads to brain gadolinium deposition in early MS. Zivadinov R, Bergsland N, Hagemeier J, Ramasamy DP, Dwyer MG, Schweser F, Kolb C, Weinstock-Guttman B, Hojnacki D. Neurology. 2019 Jul 8. pii: 10.1212/ WNL.0000000000007892.doi:10.1212/WNL.0000000000007892. [Epub ahead of print] • Guidance on gadolinium-based contrast agent administration to adult patients. RCR, April 2009 • Updated Clinical Practice Guideline on Use of Gadolinium-Based Contrast Agents in Kidney Disease Issued by the Canadian Association of Radiologists. Schieda N, Maralani PJ, Hurrell C, Tsampalieros AK, Hiremath S. Can Assoc Radiol J. 2019 Jun 26. pii: S0846-5371(19)30045-2. doi: 10.1016/j.carj.2019.04.001.[Epub ahead of print] Review. da Version 3 | © The Royal Australian Zealand and New College of Radiologists® | November 2019 Guideline on the use of Gadolinium-Containing MRI Contrast Agen

Page 11 of 14 Appendix A - Flowchart for Clinical Decision-making Guideline on the use of Gadolinium-Containing MRI Contrast Agen da Version 3 | © The Royal Australian and New Z ealand College Radiologists® November 2019

Gadolinium-based contrast agents considered low-risk forte development of NSF:

MultiHance gadobenate Linear Clariscan, Dotarem gadoterate Cyclic

Gadovist gadobutrol Cyclic

ProHance gadoteridol Cyclic

Page 12 of 14 Appendix B - Gadolinium-based MR Contrast Agent: Nomenclature

By Generic Name:

Generic Name Trade Name Manufacturer gadobenate MultiHance Bracco gadobutrol Gadovist BayerScheringPharma gadodiamide Omniscan GE Healthcare gadopentetate Magnevist BayerScheringPharma gadoterate Dotarem Guerbet Clariscan GE Healthcare gadoteridol ProHance Bracco gadoxetate Primovist BayerScheringPharma

By Trade Name:

Trade Name Manufacturer Generic Name Clariscan GE Healthcare gadoterate Dotarem Guerbet gadoterate Gadovist BayerScheringPharma gadobutrol Magnevist BayerScheringPharma gadopentetate MultiHance Bracco gadobenate

© The Royal Australian Zealand and New College of Radiologists® | November 2019 Omniscan GE Healthcare gadodiamide Primovist BayerScheringPharma gadoxetate ProHance Bracco gadoteridol da Version 3 | Guideline on the use of Gadolinium-Containing MRI Contrast Agen

Page 13 of 14 Appendix C - Chelate Properties

Ligand Relaxivity r1, Risk of NSF Trade Name Generic Name Bonding Biliary excretion Structure /s/mM, at 1.5 T

Omniscan gadodiamide Linear Non-ionic No 4.3 High

Magnevist gadopentetate Linear Ionic No 3.9 – 4.1

Limited Experience Primovist gadoxetate Linear Di-ionic 50% 6.9

MultiHance gadobenate ** Linear Ionic ~ 3 % 6.3 – 7.9 Clariscan, Dotarem gadoterate Cyclic Ionic No 3.6 Low

Gadovist gadobutrol Cyclic Non-ionic No 4.7 – 5.2

ProHance gadoteridol Cyclic Non-ionic No 4.1

** Although gadobenate has a relatively poor stability profile, clinical experience to date suggests that it has a low risk of NSF. Adapted from Nephrogenic systemic fibrosis and gadolinium-based contrast media : updated ESUR contrast medium safety committee guidelines Thomsen HS, Morcos SK, Almen T, et al, Eur Radiol. 2013 23:307-18. © The Royal Australian and New Zealand College of Radiologists® | November 2019

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