Safety of Magnetic Resonance Contrast Media

Contrast 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 group—paramagnetic 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).TABLE 1: Overview of the Commercially Available Gadolinium ChelatesBecause 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).TABLE 2: Step Concept of Drug DevelopmentAdverse 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.TABLE 3: Serious AE/Serious Drug ReactionIf 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 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.TABLE 4: Overview of the Recommended Dosages for Commercially Available GBCAsA 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 AE. These rates normally differ between the clinical studies and noninterventional studies. In phase II and phase III studies10–16 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 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 reported—6 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). 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 liver-specific 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 (>3 mg per 100 mL), the fecal excretion of gadoxetate is markedly 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 hepatic impairment the pharmacokinetics and binding of gadofosveset were not significantly influenced. the fecal of gadofosveset between hepatic impaired subjects and subjects a of but in it is not necessary to the dosage of gadofosveset in patients with impaired hepatic Owing to the of intravenous with subsequent no contrast agent should be administered in with another drug. In the of GBCAs are not evaluated. For the of the commercially available contrast agents, the manufacturers name with different are for gadoterate studies has been performed for and gadobenate However, for no was reported in the of drug data are available for gadopentetate and (Primovist) was in animal studies 11 drugs at 3 to 5 times the clinical Only when is used is there a of In there was no of drug or other with The assessment of 16 no in with gadobutrol Owing to the albumin binding of gadofosveset there is a for Gadofosveset (Vasovist) at concentrations between 0.3 and can drugs and from their binding to albumin as has been shown by in The rate was only significantly by and These studies also assessed the potential effect of and at concentrations up to 100 times the clinical adverse were at clinically relevant In no on the of another albumin binding was The of was not and the efficacy of the medicinal product was not influenced. after GBCA administration was in by et and in by et but not In et published a study the serum of patients MR after MR Of patients, a or acute in serum after the MR examination. Consequently, patients received treatment based on these without any adverse The most groups included patients with impaired renal short between the and the and the administration of a or dosages of and in their to this study that the are a of the and with the and not a should be of these potential and this potential with their clinical to this et the of after the administration of GBCA of They assessed gadopentetate and with to possible with serum For and a clinically with for was of possible should be when using for total iron binding and in serum Magnetic resonance imaging is very and for imaging to However, up to the safety and the of gadolinium-based contrast agents is very The of the contrast agents differ in their for the administration of GBCA in Some manufacturers their use only the of because no clinical trials have been performed to their safety profile in on local gadopentetate (Magnevist) is approved in 2 for the imaging of the and In some such as the for the of gadopentetate in is to the In the approved for this group include imaging in the United and the United to the product is not recommended in 2 because of a lack of data on safety and In not be administered with an but by to for body the total body clearance of is in the group 2 to 11 in the a of the of for patients 2 to 11 and to compared with the adult et in a study with 16 healthy not They recommended no adjustment in dosage for patients 2 to that for Gadoterate (Dotarem) is approved in some for patients at a dose of 0.1 mmol per kilogram of body studies have been performed using gadoterate as contrast agents in for different for example, or study the safety in be In studies were for the of in and et included 6 to in in a phase III trial at a dose of 0.1 mmol per kilogram of body AE was experienced by patients. Two patients slightly possibly related to the contrast agent. clinically relevant changes the rate and the after injection were A phase III trial evaluated the safety aspect of the administration of in 6 with a control group of serious AE patients changes in the safety parameters and The control group Only 3 clinically relevant AEs of and in the contrast group and 1 in the control group were A review of the safety and efficacy of and gadopentetate (Magnevist) of patients to received the first and patients received the second contrast agent at 0.1 mmol per kilogram of body weight was published by et in Adverse events for gadopentetate were reported for patients and patients for The results of phase I to III studies at from 0.1 to 0.3 mmol per kilogram of body weight of including patients, that the drug be safely of the The most safety data are available for for and These that this GBCA is safe and well with no increased Similar results were obtained for gadopentetate (Magnevist) and In the group 2 the safety criteria Although data are for gadoterate administrations in to be and A recent study that no dose adjustment of the adult dose of gadobutrol based on body weight is necessary in the between 2 to Gadofosveset gadobenate (Multihance), and gadoxetate (Primovist) should only be used in patients With regard to the the European has new for the use of GBCA, which are based on a between of GBCA and GBCA (Table for the administration in and are GBCA not be used in 4 are to have kidneys. In up to 1 of the dose should be to the and GBCA should be used in as well as in only at The for for of the European of NSF This new was for the first time and published in 2000 by et In a possible between gadolinium-based MR contrast agents and a new as This systemic can potentially also the and for GBCAs are considered a potential factor in the of The are in the and are reported. The is NSF was as an AE with GBCA, all AEs with GBCA administration were of the or They occurred after the majority the of of such events by was very high because they occurred the patient was still in the they were and clinically if treatment was the treatment was given by The events were or to systemic fibrosis an different temporal systemic fibrosis occurred at least many but or even to The was and is almost by the Most have a patient with NSF not only because the is but also because the patients have the before the systemic fibrosis almost in patients with markedly impaired renal function rate 30 per or in with acute renal such as are patient worldwide of The reported incidence in patients with severe renal impairment and is between to and up to in patients with a 15 per not all commercially available GBCAs to be with The most review of reported of of whom were with the administration of with gadopentetate (Magnevist), and 3 with extensive there is up to no for the of NSF after the administration of GBCA. potential and have been but there to has been no for the of this Gadolinium-based contrast agent can be according to their and they are and (Table 1). They can be further by their chemical as of in reference to the of the gadolinium the binding in the there is a for the gadolinium to from The gadolinium as well as the are available to with other This of of the gadolinium is as Owing to the that gadolinium is and gadolinium was found in in NSF patients, the that there is a between the of GBCA and NSF was of gadolinium in and the of NSF by The with renal impairment is by the longer times and prolonged time in patients with severe renal found in these patients, be a for In this context, the and of are The or chemical is an important factor with to the for the Contrast agents are characterized by their at of and their at the physiological of Table 1 an overview for the commercially available gadolinium-based contrast that these parameters are for the description of gadolinium-based contrast agents but are for the With regard to the special of contrast agents, a of more can be estimated under physiological for all 3 relevant in to be The of differ between and In the first the GBCAs and have to the of gadolinium This is necessary because of the of the compared with the In the of the GBCAs is compared with that of the this to be by the of of NSF almost with GBCA. The European and US regulatory have to the in patients with severe impaired renal Therefore, all product a of These that the for the MR should be and MR or other imaging should be considered. In it is recommended to the renal function before the administration of GBCA and to the patients at on the patients at with a severe renal impairment 30 per should be administered a gadolinium-based contrast agent. the of GBCA should be used in the possible consistent with a diagnostic quality Dosages a single dose should be In case of required of GBCA, a for should be and the times should be An of between 2 is recommended by the Although there are no data to that can most that patients have MRI should after the administration of GBCA. et have that of GBCA can be enhanced by rates were and in the first to systemic fibrosis has a very in the of GBCA. This is given the and potential severity of the given the lack of any proven it should be that NSF is a very and other GBCA AEs (Table With to NSF other AE, GBCA should be given they are and only if the potential of an the of AE. The is also the patient from the should be but it should not administration of GBCA. It should be a to The occurrence of NSF has to almost There have been no with clinical of since Therefore, the data reported by at the for Magnetic in in are still very (Table all should the of the to the possible MR diagnostic for their for example, the published by the US and Drug and the European for the of

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