Safety of magnetic resonance contrast media: a review with special focus on nephrogenic systemic fibrosis.

REVIEW ARTICLE

Safety of Magnetic Resonance Contrast Media A Review With Special Focus on Nephrogenic Systemic Fibrosis Stefan Haneder, MD,* Walter Kucharczyk,Þ Stefan Oswald Schoenberg,* and Henrik Jakob Michaely, MD*

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ontrast agents are an integral part of clinical magnetic resonance imaging (MRI) examinations.1 They improve the diagnostic value of MRI examinations in almost every body region, and they enable certain MRI examinations that would otherwise not be possible. Magnetic resonance imaging contrast agents can be classified according to their chemical structures, their effect on the local magnetic field, or by their contrast mechanism. Two main groups of contrast agents are commercially available as follows: paramagnetic and superparamagnetic.1 An example of an agent from the second group is superparamagnetic iron oxide2 such as ferucarbotran (Resovist, Bayer HealthCare Pharmaceuticals, Berlin, Germany), an agent used in the detection and characterization of focal liver lesions.3 Most of the contrast agents however belong to the first groupVparamagnetic contrast agents containing either gadolinium or manganese. Owing to their worldwide dominance in clinical practice, this article will focus on the gadolinium-based contrast agents (GBCAs). Table 1 gives an overview of the commercially available GBCA in Europe. Some of these are not approved for use in the United States (Table 1). Because contrast agents are diagnostic aids and not therapeutic agents, special emphasis is put on safety and tolerability. Gadolinium-based contrast agents, combining a high diagnostic value with an excellent safety profile, fulfill these criteria very well. However, the recent recognition of the association between nephrogenic systemic fibrosis and GBCA has alerted the medical community that the safety profile of GBCA, although still excellent, is not perfect. This article will provide review of the different safety aspects of the currently available GBCAs with a special emphasis on nephrogenic systemic fibrosis (NSF) (Table 2). Adverse events (AEs) are defined as any untoward medical occurrence in a patient administered a medicinal product. It is not necessary to show a causal relationship, only a temporal association. Under AE, any unfavorable and unintended signs, symptoms or diseases are subsumed. If the one of the circumstances listed in Table 3 is applicable, the AE is termed a serious adverse event. If a causal relationship between the medical product and the AE or the serious AE is shown or is at least a reasonable possibility, the event is classed as an adverse drug reaction or serious adverse drug reaction. The different terminology of event as opposed to reaction emphasizes the relationship. For regulatory reporting purposes, if an event is spontaneously reported, even if the relationship is unknown or unstated, it is defined as an adverse drug reaction. The guideline defines an additional terminology of unexpected adverse drug reaction. This term is used if the nature, severity, specificity, or outcome of the adverse drug reaction From the *Department of Radiology, University Hospital of Cologne, Cologne, Germany; University Medical Center Mannheim, Heidelberg University, Mannheim, Germany; and †University of Toronto, Toronto, Canada. Reprints: Stefan Haneder, MD, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Theodor-Kutzer-Ufer 1-3, 68167 Mannheim, Germany (e-mail: [email protected]). The authors declare no conflict of interest. Copyright * 2015 Wolters Kluwer Health, Inc. All rights reserved.

Top Magn Reson Imaging

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is not consistent with the term or description in the local/ regional product labeling. In the case of uncertainty by the marketing authorization holder, the adverse drug reaction is termed uncertain. The term suspected unexpected adverse drug reaction is defined as an unexpected adverse drug reaction, which is classified as serious and a probable reaction on the administered drug. Most literature does not adhere to this terminology and subsumes everything under the term adverse events. Although most authors grade the severity of AE as serious or not serious (or mild, moderate, or severe) most of the articles lack clear definitions of their terminology.

SAFETY PROFILES OF CURRENT COMMERCIALLY AVAILABLE GBCAs Dosage and Injection Rate The assessment of the recommended dosage of a contrast agent is an important part of the marketing approval. Key aspects are exemplarily delineated for the contrast agent gadobutrol (Gadovist/Gadavist). Before the first human clinical studies, initial animal experiments are performed, whereby safety parameters such as the acute intravenous lethal median dose (LD50) are evaluated. For gadobutrol, the LD50 in preclinical rat studies was 30 mmol/kg.4 In early clinical studies, phase I, different concentrations were investigated to probe the tolerability and the pharmacokinetics in healthy volunteers. Single intravenous administrations of gadobutrol between 0.04 and 0.5 mmol per kilogram of body weight were well tolerated.4 In another preclinical phase I study including healthy volunteers, dosages up to 1.5 mmol per kilogram of body weight of gadobutrol were proven to be well tolerated.5 These preclinical data demonstrated that the currently recommended dosage of up to 0.3 mmol per kilogram of body weight had a large safety range, which in times before NSF was found to be safe even in patients with chronic renal impairment.6 The currently recommended dosages of the commercially available GBCAs for Europe are summarized in Table 4. A second important clinical aspect of the intravenous injection of GBCA is the injection rate. Some manufacturers provide a range of possible injection rates (Table 4). For the exemplary chosen gadobutrol (Gadovist/Gadavist), there is no general recommendation for the injection rate. Studies of different injection rates are for the most part determined by the quality of images, for example, which rates produce the best MR angiograms or best time-resolved MR angiography. Kramer et al7 evaluated injection rates of gadobutrol between 0.2 and 0.8 mL/s without complications. Similarly, no clinically relevant changes in safety parameters were found in a study dealing with the safety of gadobutrol enhanced MR angiography using flow rates between 0.2 and 2.0 mL/s.8 In a comparison study of gadobutrol and gadopentetate (Magnevist), injection rates of even up to 5 mL/s were safely used.9

Adverse Events in Commercially Available GBCA A general indicator for the assessment and the comparison of the general safety of contrast agents is the rate of reported

Volume 24, Number 1, February 2015

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Manufacturer

Bayer HealthCare Pharmaceuticals, Berlin, Germany Bracco Altana, Konstanz, Germany GE Healthcar, Braunschweig, Germany Mallinckrodt Inc, St. Louis Bayer HealthCare Pharmaceuticals, Berlin, Germany Lantheus Medical Imaging, North Billerica, MA Guerbet, Roissy, France Bayer HealthCare Pharmaceuticals, Berlin, Germany Bracco Altana, Konstanz, Germany

Short Name

Gadoteridol Gd-HP-DO3A

Gadoterate Gd-DOTA Gadobutrol Gd-BT-DO3A

Gadofosveset

Gadoversetamide Gd-DTPA-BMEA Gadoxetate Gd-EOB-DTPA

Gadodiamide Gd-DTPA-BMA

Gadobenate Gd-BOPTA

Gadopentetate Gd-DTPA

Renal

Renal

Renal

91% renal, 9% biliar


Renal

Renal


Renal

Nonionic

Nonionic

Ionic

Ionic

Ionic

Nonionic

Nonionic

Ionic

Ionic

Net Charge

23.8

21.8

25.6, 25.8

22.1, 23.2

23.5

16.6

16.9

22.6

22.5

Thermodynamic Stability Constant

17.2, 17.1

15.5

19.3, 18.8

18.9, 19.2

18.7

15.0

14.9

18.4

18.4

0.1/0.23

0/NA

0/none

0.1/NA

0.5/NA

10/28.4

5/12

0/0.4

0.1/0.4

Excess Ligand, Percentage of Molar Concentration of Gd Complex, mg/mL

3h

24 h

91 mo

NA

NA

NA

35 s

NA

10 min

Dissociation Half Life at pH = 1.0

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ProHance*

Gadovist/ Gadavist‡

Dotarem†

Ablavar*

Primovist*

Optimark*

Omniscan*

Multihance*

Magnevist*

Brand Name

Elimination Pathway

Conditional Stability at pH = 7.4



*Food and Drug AdministrationYapproved contrast agents. †Also approved in the United States since March 2013. ‡In the US market. NA, not available.

Macrocyclic

Linear/ acyclic

Chemical Structure

TABLE 1. Overview of the Commercially Available Gadolinium Chelates

Haneder et al Volume 24, Number 1, February 2015

* 2015 Wolters Kluwer Health, Inc. All rights reserved.


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TABLE 2. Step Concept of Drug Development Phase Initial studies to estimate the initial safety and tolerability, to I determine pharmacokinetics, to assess pharmacodynamics, to early measure the drug activity, and to gain early evidence of effectiveness; may include healthy participants and/or patients. Phase Controlled clinical studies conducted to evaluate the effectiveII ness of the drug for a particular indication or indications in patients with the disease or condition under study and to determine the common short-term adverse effects and risks; relatively narrow criteria, leading to a quite homogenous study population. Phase Expanded controlled and uncontrolled trials after preliminary III evidence suggesting effectiveness of the drug has been obtained and are intended to gather additional information to evaluate the overall benefit-risk relationship of the drug and provide and adequate basis for physician labeling. Phase Postmarketing studies to delineate additional information IV beyond the previous demonstration of the drug’s safety, efficacy, optimal use, and dose definition.

AE. These rates normally differ between the clinical studies and noninterventional studies. In phase II and phase III studies10Y16 of gadofosveset for example, a total of 767 patients were included. Of these 767, 276 patients (36%) reported 511 AE, and 4 patients (0.5%) had a serious AE. Of these AEs in 176 patients, 283 were treatment related, of which the majority was rated as mild (233 AEs). The overall rate of AEs in the placebo comparison group with 49 patients was 44 AEs in 23 patients (46.9%). The AEs of 16 patients (32.7%) were considered treatment related. The safety data on many GBCA are published. Owing to the longer marketing authorization of these contrast agents, the reviews include data of larger phase IV and postmarketing surveillance studies. The rates of adverse and serious AEs are given without stratification to dosage or type of examination. Safety data for gadobenate (Multihance), gadoterate (Dotarem) and gadopentetate (Magnevist) are shown in the following sections.

Gadobenate (Multihance) In 79 performed clinical trials up to 2004, 2982 patients had received gadobenate.17 Of these 2982 patients, 413 (14%) experienced at least 1 AE definitely or potentially related to the contrast agent. Of these AEs, 317 (11%) were rated as mild. Similar rates were observed in control groups, 17% mild AEs in the control group in 127 patients. The overall rate of AEs in all 850 patients included in active or placebo control groups were slightly lower. Similar results were obtained in an earlier review of the safety assessment of gadobenate by Kirchin et al,18 which included 2891 subjects studied between 1990 and 2000 in 69 clinical trials, overlapping the study by Shellock et al.17 The overall incidence of AE was 19.8%, of which 15.1% were potentially related to the contrast agents in adult subjects. In their review article, Shellock et al17 published the spontaneous reported AE after approximately 1.5 million patients received gadobenate. From the marketing approval in 1997 in Europe to July 2005, 1539 AE were reported in 761 patients, yielding an estimated AE rate of 0.05%. Most of the AEs were not serious. Serious AEs were observed in only 147 patients (0.01%). Herborn et al19 assessed the safety data for gadobenate in 38,568 patients in a large observational study in 662 German centers from 1998 to 2006. Adverse events were observed

Safety of MR Contrast Media

in 459 patients (1.2%), none of whom required medical intervention. Of these, the potential relationship to gadobenate occurred in 298 patients (66.5%), and a definitive one occurred in 83 patients (18.5%). An additional 11 patients (0.03%) reported serious events, of whom 6 were considered definitely related to gadobenate and 2 were possibly related.

Gadoterate (Dotarem) In a double-blind study of 1038 patients, the safety and efficacy of gadoterate were compared with gadopentetate for imaging of the central nervous system (CNS). Of the patients, 0.97% (gadoterate) and 0.77% (gadopentetate) reported an adverse reaction, but no serious AEs were reported.20 A similar tolerance was assessed in 300 neurologic patients comparing gadoterate and gadopentetate. Adverse events were found in 17.3% of the gadoterate group and 19.3% for the gadopentetate group.21 An observational study by Herborn et al22 including 24,308 patients between 2004 and 2005 evaluated the clinical safety of gadoterate. Ninety-four patients (0.4%) had at least 1 AE. Of these patients, 24 (25.5%) required further medical treatment, and 1 (1.1%) had to be hospitalized. Most of the reactions (63, 67%) were regarded as most likely related to the administration of gadoterate. In 1 case (0.004%), a serious AE with complete recovery was reported. Maurer et al23 published similar results in the follow-up study with 84,621 patients, presenting a rate of AE of 0.34%.

Gadopentetate (Magnevist) Gadopentetate is the longest commercially available contrast agent. It has been on the market since 1988. Multiple trials have investigated the safety and efficacy of gadopentetate. Owing to this extensive experience, gadopentetate has served as the standard of reference for many subsequent contrast agent trials. In early US clinical trials including 1068 patients at a dose of 0.1 mmol/kg, 213 patients (19.9%) experienced 1 or more clinical adverse reactions. Most of these reactions were minor and short lived. Twenty-five adverse reactions were rated as severe, and only 2 of these were possibly or probably related to the study drug.24 In an open-label, prospective postmarketing surveillance study with 15,496 patients in 1992, AE occurred in 372 patients (2.4%).25 Two serious AEs were observed but not attributed to gadopentetate. Between 1994 and 2002, 4046 subjects in 117 studies received gadopentetate for MR angiography.26 Only in 1 phase III clinical trial were adverse reactions reportedV6 mild adverse reactions occurred in 3 of 15 patients but without attribution to the contrast agent. In the rest of the studies, no AEs were reported. Knopp et al27 assessed the pharmacovigilance data of gadopentetate based on the spontaneous reported AEs after 45 million administrations. The most frequent types were subjective symptoms (11.61%), followed by vomiting, urticaria, and mucosal reactions (5.45%, 5.39%, 4.95%, respectively). TABLE 3. Serious AE/Serious Drug Reaction Any Untoward Medical Occurrence at Any Dose, Which 1. Result in death 2. Is life threatening 3. Requires inpatient hospitalization or results in prolongation of existing hospitalization 4. Results in persistent or significant disability/ incapacity 5. Is a congenital anomaly/birth defect 6. Is a medically important event or reaction



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TABLE 4. Overview of the Recommended Dosages for Commercially Available GBCAs

Brand Name

Short Name

Molarity, mmol/mL

Magnevist

Gadopentetate Gd-DTPA

0.5

Multihance

Gadobenate Gd-BOPTA Gadodiamide Gd-DTPA-BMA

0.5

Omniscan

Optimark

Primovist Ablavar

Gadoversetamide Gd-DTPABMEA Gadoxetate Gd-EOB-DTPA Gadofosveset

0.5

Indications Brain, spine and associated tissue; head and neck; whole body (excluding the heart) Liver, CNS

Dosage Dosage (Indication (Indication Dependent), Dependent), mmol per mL per kg of Body kg of Body Weight Weight

Injection

Approval in Pediatrics (Europe)

0.1

0.2

Up to 10 mL per 15 s

1. Indication dependent, all age groups27 2. 92 y34

0.05Y0.1

0.1Y0.2

0.05Y0.1

0.1Y0.2

Bolus or slow injection (10 mL/min) NA

96 mo

0.1Y0.3

0.2

Bolus

92 y

None

0.5

Brain, spine and associated tissue; head and neck; whole-body (excluding the heart) Liver, CNS

0.25

Liver

NA

0.1

2 mL/s

None

0.25

MRA (abdomen, lower extremities) Brain, spine and associated tissue; liver, kidneys, pancreas, pelvis, lung, heart, breast, muskuloskeletal system, MRA Brain, spine, kidney, MRA Brain, spine and associated tissue; head and neck

0.03

0.12

Bolus

None

0.1

0.2

3Y5 mL/min; MRA: up to 120 mL/min

All age groups, excluding MRA

0.3

0.1Y0.3

NA

97 y

0.1

0.2

Dotarem

Gadoterate Gd-DOTA

0.5

Gadovist/ Gadavist ProHance

Gadobutrol Gd-BT-DO3A Gadoteridol Gd-HP-DO3A

1.0 0.5

10Y60 mL/min 92 y (only CNS) or bolus 960 mL/min

NA, not available; MRA, magnetic resonance angiography.

All of these studies demonstrate that GBCAs are safe drugs in the general patient population. Adverse events are uncommon, and when they occur, they are mild and resolve spontaneously in almost all cases. Typically mild AEs are headache, nausea, taste perversions, vasodilatations, and injection site reactions.

SPECIAL SAFETY ASPECTS OF GBCAs Patients With Impaired Liver Function Most GBCAs are eliminated by the kidneys. Only the liverspecific contrast agent gadoxetate (Primovist) is eliminated renally and hepatically in equal parts. Gadobenate (Multihance) and gadovosfeset (Vasovist) also have some hepatic excretion, but this is minor (Table 1). Consequently, hepatic impairment is not a limiting factor for the administration of GBCA. Owing to the dual excretion pathway (renal and hepatic) of gadoxetate (Primovist), compensation by the remaining pathway is possible if the other pathway is impaired.28 There is no increased rate of AE in patients with impaired hepatic function. In patients with hepatic impairment and high bilirubin (93 mg per 100 mL), the fecal excretion of gadoxetate is markedly

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reduced, but total serum clearance and terminal half time is not significantly influenced. In patients with severe hepatic impairment, a compensatory shift in the extent of urinary excretion is observed. Therefore, no adjustment of dosage is necessary in patients with hepatic impairment, for gadoxetate or gadobenate (Multihance). A new aspect of the hepatic function arises with regard to the albumin binding character of some gadolinium-based contrast agent. This applies predominantly to gadofosveset, which was introduced as Vasovist. Gadofosveset is currently not available in the European market, but manufactured in the US under the name Ablavar. Gadofosveset is characterized by a transient, reversible, and noncovalent binding to serum albumin because of a lipophilic side chain and leads to a prolonged imaging time, up to 60 minutes after injection of a single dose.14,29 In this context, the quantity of serum albumin, which is competitively available for binding for gadofosveset as well as for physiological processes, should be considered. In patients with a moderate hepatic impairment (Child Pugh B), the plasma pharmacokinetics and protein binding of gadofosveset were not significantly influenced. Comparing the fecal elimination of gadofosveset between hepatic impaired subjects (2.7%) and normal subjects (4.8%), a slight decrease of * 2015 Wolters Kluwer Health, Inc. All rights reserved.



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elimination occurs, but in general, it is not necessary to adjust the dosage of gadofosveset in patients with impaired hepatic function.30

DrugYDrug Interactions Owing to the risk of intravenous precipitate formation with subsequent vascular occlusion, no contrast agent should be administered contemporaneously in combination with another drug. In general, the drugYdrug interactions of GBCAs are not thoroughly evaluated. For the minority of the commercially available contrast agents, the manufacturers explicitly name interactions with different drugs. No interactions are described for gadoterate (Dotarem). No formal interaction studies has been performed for gadodiamide (Omniscan),31 gadoversetamide (Optimark)32 and gadobenate (Multihance).33 However, for gadobenate, no interaction was reported in the course of drug development. No data are available for gadopentetate (Magnevist)34 and gadoteridol (ProHance).35 Gadoxetate (Primovist) was tested in animal studies (rats) against 11 drugs at 3 to 5 times the clinical dose.36 Only when Rifampicin is used is there a significant decrease of enhancement. In vivo, there was no obvious evidence of drug interaction or other incompatibilities with gadodiamide. The assessment of 16 pharmaceuticals showed no significant in vitro incompatibility with gadobutrol (Gadovist/Gadavist).37 Owing to the reversible albumin binding of gadofosveset (Vasovist), there is a theoretical source for interaction. Gadofosveset (Vasovist) at concentrations between 0.3 and 0.9 mmol/L can displace several common drugs (digitoxin, propranolol, verapamil, and warfarin) from their binding to albumin as has been shown by in vitro experiments. The relaxation rate was only significantly decreased by naproxen and ibuprofen. These studies also assessed the potential effect of warfarin, ibuprofen, digitoxin, diazepam, ketoprofen, naproxen, diclofenac, piroxicam, and phenprocoumon at concentrations up to 100 times the clinical steady-state plasma concentrations. No adverse interactions were stated at clinically relevant concentrations.30 In vivo, no affect on the unbound fraction of warfarin, another albumin binding drug, was found. The anticoagulant activity of warfarin was not altered, and the efficacy of the medicinal product was not influenced.

Caloric Ca2+ Determination Spurious hypocalcemia after GBCA administration was described in 1995 by Normann et al38 and in 1999 by Lin et al39 but not widely known. In 2003, Prince et al published a study evaluating the serum calcium level of 896 patients (1049 MR examinations) after gadodiamide (Omniscan)Yenhanced MR examinations. Of 896 patients, 48 (4%) showed a critical hypocalcemia or acute reductions (92 mg/dL) in serum calcium after the MR examination. Consequently, 18 patients received improper treatment based on these laboratory findings, albeit without any adverse effects. The most ‘‘vulnerable’’ groups included patients with impaired renal function, short periods between the examination and the blood sampling, and the administration of a double or triple dosages of gadodiamide (0.2Y0.3 mmol/kg). Choyke and Knopp40 emphasized in their comment to this study that the laboratory findings are a consequence of the testing method rather than true hypocalcemia. Gadodiamide and gadoversetamide interfere with the sampling assay and do not cause a real hypocalcemia. Nevertheless, radiologists should be aware of these potential misleading laboratory findings and communicate this potential problem with their clinical colleagues. Contributing to this process, Proctor et al41 broached the issue of falsely abnormal laboratory test findings after the administration of GBCA (American Journal of Clinical Pathology, 2004). They assessed gadodiamide, gadoversetamide,


gadopentetate dimeglumine, and gadoteridol, with respect to possible interference with multiple serum assays. For gadodiamide (Omniscan) and gadoversetamide (Optimark), a clinically significant negative interference with colorimetric assays for calcium was described. Caution of possible interference should be exercised when using colorimetric assays for angiotensin-converting enzyme, calcium, iron, magnesium, total iron binding capacity, and zinc in serum samples.

Pediatric Applications Magnetic resonance imaging is very useful and attractive for pediatric imaging owing to its lacking radiation exposure. However, up to now, the safety and long-term information concerning the pediatric application of gadolinium-based contrast agents is very limited. The enclosed labels of the current contrast agents differ in their recommendations for the administration of GBCA in children. Some manufacturers recommend their use only beyond the age of 18 years because no clinical trials have been performed to evaluate their safety profile in pediatrics. Depending on local regulations gadopentetate (Magnevist) is approved in children older than 2 years for the imaging of the CNS and whole-body imaging.27 In some countries such as Germany, the indication for the application of gadopentetate in newborns is restricted to the CNS. In contrast, the approved indications for this age group include whole-body imaging in the United Kingdom and the United States.27 According to the product information, gadoversetamide (Optimark) is not recommended in children younger than 2 years because of a lack of data on safety and efficacy.32 In children, gadoversetamide must not be administered with an autoinjector but by hand to avoid overdosage. Corrected for body weight, the total body clearance of gadoversetamide is greater in the age group 2 to 11 years than in the older groups. Furthermore, a shortening of the elimination half-life of gadoversetamide occurs for patients 2 to 11 years and 12 to 18 years compared with the adult population.32 Baker et al42 in a study with 16 healthy children did not find age-related changes. They recommended no adjustment in dosage for patients older than 2 years relative to that for adults. Gadoterate (Dotarem) is approved in some countries for patients younger than 18 years at a dose of 0.1 mmol per kilogram of body weight. Several studies have been performed using gadoterate as contrast agents in children for different diseases, for example, juvenile rheumatoid arthritis43 or sickle cell anemia.44 No dedicated study concerning the safety in children could be found. In contrast, several studies were conducted for the evaluation of gadodiamide (Omniscan) in children and infants. Hanquinet et al45 included 50 children 6 months to 13 years in age in a phase III trial at a dose of 0.1 mmol per kilogram of body weight. No AE was experienced by conscious patients. Two sedated patients showed slightly abnormal movements, possibly related to the contrast agent. No clinically relevant changes regarding the heart rate and the venous blood pressure after injection were noted. A phase III multicenter trial evaluated the safety aspect of the administration of gadodiamide (Omniscan) in 39 infants younger than 6 months, with a control group of 20 infants. No serious AE occurred.46 Eighteen patients (51.4%) showed 31 abnormal changes in the safety parameters (blood, urine, heart rate, and oxygen saturation). The control group revealed 19 abnormal findings (80%). Only 3 clinically relevant AEs (elevation of serum-alanine aminotransferase, serum-aspartate aminotransferase, and bilirubin) in the contrast group and 1 in the control group (vomiting) were noted.



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A review of the safety and efficacy of gadodiamide (Omniscan) and gadopentetate (Magnevist) of 353 patients (15 days to 18 years), who received the first and 128 patients (2Y18 years) who received the second contrast agent at 0.1 mmol per kilogram of body weight was published by Lundby et al47 in 1996. Adverse events for gadopentetate were reported for 13 patients (4%) and 8 patients (6%) for gadodiamide. The results of phase I to III studies at doses ranging from 0.1 to 0.3 mmol per kilogram of body weight of gadoteridol (ProHance), including 119 pediatric patients, indicated that the drug could be safely injected irrespective of the age.48 The most comprehensive safety data are available for gadodiamide (Omniscan) for children, infants, and neonates. These suggest that this GBCA is safe and well tolerated, with no increased risk. Similar results were obtained for gadopentetate (Magnevist) and gadoteridol (ProHance). In the age group older than 2 years, gadoversetamide (Optimark) fulfilled the safety criteria too. Although valid data are missing for gadoterate (Dotarem), administrations in children seem to be tolerable and safe. A recent study suggests that no dose adjustment of the adult dose of gadobutrol based on body weight (0.1 mmol/kg) is necessary in the pediatric population between 2 to 17 years.49 Gadofosveset (Vasovist), gadobenate (Multihance), and gadoxetate (Primovist) should only be used in patients older than 18 years. With regard to the NSF, the European Medicines Agency (EMA) has developed new guidelines for the use of GBCA, which are based on a distinction between low-risk of mediumrisk GBCA and high-risk GBCA (Table 5/6).50 Therein recommendations for the administration in newborn babies and infants are given. High-risk GBCA must not be used in newborn babies younger than 4 weeks, who are known to have immature kidneys. In infants up to 1 year of age, the dose should be restricted to the minimum dose. Low-risk and medium-risk GBCA should be used in newborn babies as well as in infants only at minimum dosages.

NEPHROGENIC SYSTEMIC FIBROSIS This new skin disease was recognized for the first time and published in 2000 by Cowper et al.51 In 2006, Grobner 52 discussed a possible link between gadolinium-based MR contrast agents and a new disease, known as NSF. This systemic disease can potentially also involve the heart, diaphragm, pleura, pericardium, and kidneys for example.53,54 GBCAs are considered a potential factor in the multifactorial etiology of NSF.54Y57 The characteristic lesions are in the skin: thickening, induration, and tightening are reported. The disease is occasionally lethal.53 Until NSF was recognized as an AE associated with GBCA, virtually all AEs associated with GBCA administration were of the allergic or vasovagal type. They occurred immediately after injection, the vast majority within minutes. Thus, the level of awareness of such events by radiologists was very high because they occurred while the patient was still in the radiology department, they were immediate and clinically obvious, and, if treatment was indicated, the treatment was usually given by radiologists. The events themselves were often self-limited or responded quickly to appropriate treatment. Nephrogenic systemic fibrosis showed an entirely different temporal profile. Nephrogenic systemic fibrosis never occurred immediately, usually taking at least many weeks but often months or even years to manifest clinically. The diagnosis was less obvious and is almost always made by doctors outside the radiology department. Most radiologists have never seen a patient with NSF not only because the disease is rare but also because the patients have left the radiology department long before the disease begins.

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TABLE 5. The Committee for Medicinal Products for Human Use of the European Medicines Agency Recommendations For Low-Risk and Medium-Risk GBCA

For High-Risk GBCA

Warnings should be added to the They must not be used in patients prescribing information for their with severe kidney problems, use in patients with severe kidin patients around the time of ney problems and patients reliver transplantation, and in ceiving a liver transplant newborn babies G4 wk of age, who are known to have immature kidneys Their doses should be restricted Their doses should be restricted to the minimum recommended to the minimum recommended dose in patients with severe dose in patients with moderate kidney problems, patients around kidney problems and infants the time of liver transplantation, up to 1 y of age, and there should and neonates and infants up to be at least a period of 7 d be1 y of age, and there should be at tween scans least a period of 7 d between scans The decision to continue or sus- As a precaution, breastfeeding pend breastfeeding for at least should be discontinued for at 24 h after a scan should be taken least 24 h after the patient has by the doctor and the mother received a high-risk agent Screening for kidney problems All patients should be screened using laboratory tests is recfor kidney problems using labommended for all patients beoratory tests before receiving fore receiving these agents these agents

Nephrogenic systemic fibrosis occurs almost exclusively in patients with markedly impaired renal function (glomerular filtration rate [GFR] G 30 mL/min per 1.73 m2) or in those with acute renal insufficiency such as hepatorenal syndrome. Confirmed cases are far less than 1000 patient worldwide (as of December 2009). The reported incidence varies in patients with severe renal impairment and is between 3% to 7% and up to 18% in high-risk patients with a GFR less than 15 mL/min per 1.73 m2.54 Yet, not all commercially available GBCAs seem to be equally associated with NSF. The most detailed review of Broome58 reported 190 biopsy-proven cases of NSF, of whom 157 cases were associated with the administration of gadodiamide (Omniscan), 8 with gadopentetate (Magnevist), and 3 with gadoversetamide (Optimark). Despite extensive research, there is up to now no conclusive explanation for the inconsistent development of NSF after the administration of GBCA. Many potential triggers and mechanisms have been examined, but there to date has been no unifying explanation for the pathogenesis of this disease. Gadolinium-based contrast agent can be subdivided according to their net charge and whether they are ionic and nonionic (Table 1). They can be further categorized by their chemical structures as ‘‘linear’’ of ‘‘macrocyclic,’’ in reference to the molecular structure of the gadolinium chelates.1,59 Despite the strong binding complex in the chelate, there is a small propensity for the gadolinium to separate from its ligand. The ligand-free gadolinium ions as well as the gadolinium-free chelates are theoretically available to interact with other intrinsic agents. This phenomenon of replacement of the gadolinium is known as transmetallation.59Y61 Owing to the fact that chelate-free gadolinium is toxic and gadolinium was found in skin biopsies in NSF patients, the hypothesis that there is a connection between the stability of GBCA and NSF was generated. Deposition of chelate-free gadolinium in tissue and organs might stimulate the development of NSF by inducing fibrosis.61 The proportional * 2015 Wolters Kluwer Health, Inc. All rights reserved.



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TABLE 6. Overall Number of NSF Cases GBCA Omniscan Magnevist Optimark Multihance ProHance Dotarem Ablavar Gadovist/Gadavist Primovist

No. Reports Unconfounded Cases Confounded Cases Estimated No. Administration Risk-Level by EMA* 369 125 20 7 8 1 1 1 0

327 43 9 0 1 0 0 0 0

increasing risk with increasing renal impairment is theoretically explained by the longer circulation times and prolonged elimination half-life time in patients with severe renal impairment. Furthermore, acidosis, often found in these patients, may be a copredictor for NSF.1,54 In this context, the characteristics and properties of Gd-chelates are meaningful. The linear or cyclic chemical structure is an important factor with respect to the stability for the Gd-complex. Contrast agents are mainly characterized by their thermodynamic stability constant at pH of 14 (log Ktherm) and their calculated conditional stability constant at the physiological pH of 7 (log Kconst). Table 1 provides an overview for the commercially available gadoliniumbased contrast agents. Schmitt-Willich55 emphasized that these parameters are sufficient for the description of linear gadoliniumbased contrast agents but are inadequate for the macrocyclic ones. With regard to the special dissociation kinetic of cyclic contrast agents, a dissociation half-time of more than 1000 years can be estimated under physiological conditions for all 3 cyclic GBCAs. Resulting relevant differences in vivo seem to be extremely unlikely. The role of excess ligands differ between linear and cyclic GBCAs.55 In the first group, the linear GBCAs gadodiamide (Omniscan) and gadoversetamide (Optimark) have excess ligands, formulated to prevent the release of gadolinium ions. This is necessary because of the reduced stability of the nonionic chelate complex, compared with the ionic ones. In conclusion, the stability of the cyclic GBCAs is much greater compared with that of the linear GBCAs. Up until now, this seems to be affirmed by the reports of unconfounded cases of NSF occurring almost exclusively with linear GBCA. The European and US regulatory authorities have released statements to strengthen the caution in patients with severe impaired renal functions. Therefore, all product labels contain a warning notice of NSF. These warnings indicate that the indication for the contrast-enhanced MR should be carefully questioned, and where possible, noncontrast MR techniques or other nonMRI imaging should be considered. In general, it is recommended to quantify the renal function before the administration of GBCA and to identify the patients at risk. Depending on the calculated GFR, patients at risk with a severe renal impairment (GFR G 30 mL/min per 1.73 m2) should be administered a cyclic gadolinium-based contrast agent. To minimize the residual circulating amount of gadolinium, GBCA should be used in the lowest possible amount consistent with obtaining a diagnostic quality study. Dosages exceeding a single dose should be avoided. In case of required readministration of GBCA, a sufficient period for elimination should be maintained, and the respective half-life times should be taken into account. An interval of 7 days between 2 applications is recommended by the EMA.50

940 million 990 million 96 million 94 million 913 million 910 million G1 million 93 million G1 million

42 82 11 7 7 1 1 1 0

High High High Medium Low Low Medium Low Medium

Although there are no data to indicate that hemodialysis can prevent NSF, most radiologists think that patients who must have contrast-enhanced MRI should receive hemodialysis immediately after the administration of GBCA. Okada et al62 have indicated that elimination of GBCA can be enhanced by repeated hemodialysis. Average excretory rates were 78.2%, 95.6%, 98.7%, and 99.5% in the first to fourth hemodialysis sessions, respectively. Nephrogenic systemic fibrosis has become a very prominent consideration in the prescription of GBCA. This is entirely understandable given the novelty and potential severity of the disease, particularly given the lack of any proven beneficial treatment. Nevertheless, it should be remembered that NSF is a very rare disease and occurs much less often than other GBCA AEs (Table 6). With respect to NSF avoidance, just like other AE, GBCA should never be given unless they are indicated and only if the potential benefit of making an accurate diagnosis outweighs the risk of AE. The converse is also trueVif the patient may benefit from GBCA-enhanced MRI, the risk should be taken into consideration, but it should not automatically preclude administration of GBCA. It should always be a ‘‘benefit to risk’’ analysis. The occurrence of NSF has diminished to almost zero. There have been no cases with clinical onset of disease since late 2008. Therefore, the data reported by Tim Leiner at the International Society for Magnetic Resonance in Medicine Annual meeting in May 2008 are still very accurate (Table 6).63,64 Nevertheless, all radiologists should keep themselves informed about the latest progress of the rare disease, NSF, to guarantee the safest possible MR diagnostic for their patient. Frequently updated Web pages, for example, www.ismrm.org, deliver the newest information published by the US Food and Drug Administration and the European Agency for the Evaluation of Medical Products.

APPENDIX 1. BACKGROUND INFORMATION

Terminology Until now, there is no clear parlance for the terminology between Europe and the United States with regard to AE. As clear, reliable, and internationally accepted terminology is mandatory, the International Conference of Harmonization aims a clarification at least among the European Union, Japan, and the United States. The International Conference of Harmonization has published in 199465 and 200366 2 documents dealing with the terminology in clinical and postapproval safety data management, which were adopted by the European Agency for the Evaluation of Medicinal Products (EMA).67,68



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Haneder et al

Pharmacovigilance After the clinical studies (phase I-III) and the marketing authorization of a new medical product, the attention and the awareness of the safety of a product decrease in the research community. However, owing to the limited extent of clinical studies, the postmarketing surveillance of medical products within their usual application in terms of the marketing authorization is an important contribution to contrast media safety. Beyond controlled clinical studies, a reporting system is established in Europe to monitor products after their marketing authorization. The basic principles for this pharmacovigilance system and the obligations for the marketing and the national authorities are published in the Guidelines on Pharmacovigilance for Medicinal Products for Human Use.69 In Europe, marketing authorization holders are obliged to collect reported AEs and to inform the national authorities. All of these information are transferred to the EMA, which provides a central acquisition, collection, and analysis via the electronic network EudraVigilance. This network uses the described consistent terminology of AEs and so on. Furthermore, the marketing authorization holder is required to provide all competent authorities with periodic safety update reports and relevant safety information from postauthorization commitments, postauthorization studies, worldwide literature, or other sources. REFERENCES 1. Dawson P. Nephrogenic systemic fibrosis: possible mechanisms and imaging management strategies. J Magn Reson Imaging. 2008;28:797Y804. 2. Reimer P, Tombach B. Hepatic MRI with SPIO: detection and characterization of focal liver lesions. Eur Radiol. 1998;8:1198Y1204. 3. Reimer P, Balzer T. Ferucarbotran (Resovist): a new clinically approved RES-specific contrast agent for contrast-enhanced MRI of the liver: properties, clinical development, and applications. Eur Radiol. 2003;13:1266Y1276. 4. Staks T, Schuhmann-Giampieri G, Frenzel T, et al. Pharmacokinetics, dose proportionality, and tolerability of gadobutrol after single intravenous injection in healthy volunteers. Invest Radiol. 1994;29:709Y715.

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