Eur. Radiol. 7 (Suppl. 5), S 243±S 245 (1997)  Springer-Verlag 1997

European Radiology

Worldwide clinical safety assessment of gadoteridol injection: an update V. M. Runge1, J. R. Parker2 1 2

Department of Diagnostic Radiology, University of Kentucky, Lexington, KY 40536, USA Department of Medical and Scientific Affairs, Bracco Diagnostics Inc., P. O. Box 5225, Princeton, NJ 08543, USA

Abstract. Gadoteridol injection is a low molecular weight chelate complex of gadolinium (III) which is useful as a contrast agent for magnetic resonance imaging. A total of 2481 adult and pediatric subjects were studied with gadoteridol at doses from 0.025 to 0.3 mmol/kg in phase I±IIIb clinical trials in Europe and the United States. The study population had a mean age of 49 years, and included 119 patients under 18 years of age and 747 patients over 60 years of age. After 2656 administered injections of gadoteridol a total of 233 adverse events were recorded in 176 exposures, an incidence rate of 6.6 % irrespective of relationship to drug administration. The most frequently reported adverse events were nausea (1.5 %), taste perversion (0.9 %), and headache (0.6 %). All other adverse events occurred with an incidence of 0.5 % or less. This report confirms the excellent safety profile of gadoteridol in healthy subjects and patients with a variety of known or suspected pathologies. Key words: Magnetic resonance (MR), contrast enhancement ± Gadolinium ± Contrast media, paramagnetic ± Contrast media, complications ± Safety

Introduction Since the first human administration of gadopentetate dimeglumine (Magnevist, Schering AG, Berlin, Germany) in November 1983 [1], contrast agents for MRI have become widely accepted for many clinical indications. The approval of Magnevist in 1986 (Europe) and 1988 (USA and Japan) was followed several years later by the approval of gadoterate meglumine (Dotarem, Guerbet Laboratories, Aulnay sous Bois, France), gadoteridol injection (ProHance, Bracco SpA, Milan, Italy) and gadodiamide injection (Omniscan, Nycomed Imaging AS, Oslo, Norway). Each of these agents is a low Correspondence to: J. R. Parker

molecular weight chelate complex of gadolinium (III) with a similar clinical effectiveness at comparable doses. As a class, the gadolinium chelates have demonstrated an excellent safety profile relative to that of other parentally administered pharmaceuticals [2]. They are well tolerated in most patients and have been shown to be relatively safe for use even in individuals traditionally considered at risk for contrast media reactions, such as patients with advanced heart disease, renal insufficiency, or those with a history of allergy or asthma [2±4]. Methods and materials A total of 2481 patients and healthy subjects were studied in phase I±IIIb clinical trials with gadoteridol in Europe and the United States. Of these, 28 were enrolled in phase I studies, 86 in a phase II study, and 2367 in phase III studies. These studies were undertaken to assess the safety and efficacy of gadoteridol at doses from 0.025 to 0.3 mmol/kg body weight for the MR study of pathology of the brain and spine, cerebral vasculature, liver, breast, head and neck, and musculoskeletal system. Gadoteridol was administered intravenously as an infusion ( < 1 cc/s) or rapid bolus ( > 1 cc/s). Safety monitoring included pre and post-contrast physical examinations, vital signs, laboratory tests, and registration of the occurrence, duration and relationship of adverse events. Results The population studied consisted of 1167 male and 1314 female subjects and patients with a mean age of 49 years (range 0.3±91.0 years). The population included 119 patients under 18 years of age (mean age 9 ± 5 years) and 747 patients over 60 years of age (mean age 68 ± 5 years). Gadoteridol was well tolerated in this population. A low incidence of clinically unremarkable changes in physical examinations, vital signs and laboratory tests was recorded. The majority of these changes were

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V. M. Runge and J. R. Parker: Worldwide safety of gadoteridol injection

Table 1. Incidence of adverse events after gadoteridol injection by country of origination, sex, age, dose administered, and injection rate Incidence (% of exposures)

Variable

Category (n = Exposures)

Number of exposures resulting in at least one adverse event

All

All exposures (n = 2656)

176

6.6

Country of origin

Europe (n = 747) United States (n = 1909)

28 148

3.7 7.8

Sex

Male (n = 1264) Female (n = 1392)

73 103

5.8 7.4

Age (years)

< 18 (n = 119) 18±60 (n = 1723) > 60 (n = 814)

4 136 36

3.4 7.9 4.4

Dose Administered (mmol/kg)

0.10 (n = 1707) 0.20 (n = 154) 0.30 (n = 765) Other (n = 30)

89 21 65 1

5.2 13.6 8.5 3.3

Injection rate

< 1 mL/s (n = 1210) > 1 mL/s (n = 822) Unknown (n = 624)

66 57 53

5.5 6.9 8.5

Table 2. Adverse events by body system after 2656 exposures to gadoteridol injection Body system (n = 2656 exposures)

Number of exposures resulting in at least one adverse eventa

Incidence (%)

All Digestive Body Special senses Cardiovascular Cutaneous Nervous Respiratory

176 59 46 30 27 22 21 10

6.6 2.2 1.7 1.1 1.0 0.8 0.8 0.4

a

Exposures resulting in more than one adverse event in a particular body system were counted only once

considered to be unrelated to the administration of gadoteridol. No consistent elevation or depression of serum iron or total bilirubin was noted in patients given gadoteridol, a finding seen previously for subjects given gadopentetate dimeglumine [5±6]. A total of 2656 injections of gadoteridol were administered to the 2481 subjects enrolled (in some protocols, some patients were studied more than once). After these 2656 injections a total of 233 adverse events (irrespective of relationship to drug administration) were recorded in 176 exposures, an incidence rate of 6.6 % (Table 1). The body systems most often affected by adverse events were the digestive system and the body as a whole (Table 2). The most frequently reported adverse events were nausea (1.5 %), taste perversion (0.9 %), and headache (0.6 %). All other adverse events occurred with an incidence of 0.5 % or less. The distribution of adverse events with respect to severity, intensity and relationship to gadoteridol administration is presented in Table 3. Most adverse events were considered mild or moderate or were not assessed for intensity. All adverse events were considered nonserious with the exception of two deaths which were both considered to be unrelated to the study drug and

one temporary episode of vasospasm which was considered to be possibly related to gadoteridol. Discussion Gadoteridol injection was first approved for marketing in the US in late 1992 and has since been approved by regulatory authorities in Japan and many European countries. In the present report, adverse events were recorded in 6.6 % of all exposures, a finding which is consistent with safety findings for other gadolinium agents as well as with earlier reports on the safety of gadoteridol. The first large series of patients studied with gadoteridol was reported in 1991 by Runge et al. [7]. Of 411 patients studied in a phase III trial, 29 (7.1 %) experienced one or more adverse events. The most commonly reported adverse events in this trial were taste disturbance (1.4 %) and nausea (1.2 %). All other adverse events occurred in one percent or less of the population studied. In a similar phase III trial of gadodiamide in patients with suspected CNS pathology, one or more adverse reactions were recorded in 46 (10.5 %) of 439 patients studied [8]. The most commonly reported reactions were headache (3.4 %), dizziness (1.8 %) and nausea (1.6 %). All other adverse events were recorded in one percent or less of the population studied. In 1995 McNamara reported results from a randomized double blind crossover study comparing gadoteridol and gadopentetate dimeglumine in patients with CNS pathology [9]. Two of 89 patients (2.2 %) receiving gadoteridol experienced an adverse event (both mild nausea), while four of 92 patients (4.5 %) receiving gadopentetate dimeglumine experienced an adverse event (injection site reaction, tachycardia, chest discomfort, and moderately severe urticaria requiring treatment). All adverse events in this trial were considered either possibly or probably related to the contrast agent administered. In a recently published overview of the clinical trial experience with gadoteridol in the United States, Olukotun

V. M. Runge and J. R. Parker: Worldwide safety of gadoteridol injection

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Table 3. Severity, intensity and relationship of adverse events after administration of gadoteridol injection (n = 2656 exposures) Parameter

Category

Number of exposures resulting in at least one adverse event (%)a

Relative frequency (% of 176 exposures resulting in at least one adverse events)b

Severity

Serious Not serious Not assessed

3 (0.1) 140 (5.3) 33 (1.2)

1.7 79.6 18.8

Intensity

Mild Moderate Severe Not assessed

157 (5.9) 23 (0.9) 0 (0) 4 (0.2)c

89.2 13.1 0 2.3

Relationship

Not related Definitely related Probably related Possibly related Remotely related Unknown relationship

27 (1.0) 50 (1.9) 13 (0.5) 54 (2.0) 5 (0.2) 38 (1.4)

15.3 28.4 7.4 30.7 2.8 21.6

a

A single exposure may have resulted in adverse events in more than one category, therefore numbers reported to not add up to 176

b

et al. reported an overall adverse event rate of 6.9 % irrespective of relationship to drug administration [5]. In this series of 1709 subjects the most commonly noted adverse events were nausea (1.4 %) and taste perversion (1.3 %), findings similar to those made in the present investigation. In a separate post-marketing series reported by Tanenbaum, 1232 patients were studied with gadoteridol at doses of 0.1 and 0.3 mmol/kg [10]. A total of 68 adverse events were recorded in 48 (3.9 %) of the patients studied. In the present report, the incidence of adverse events among patients studied with gadoteridol in European clinical trials was 3.7 %, as opposed to a 7.8 % incidence rate in the US trials (Table 1). This finding was expected, since the reported incidence of adverse events is usually higher in the United States than in Europe or Japan [3]. The incidence of adverse events was similar among men and women (5.8 % and 7.4 %, respectively, P > 0.05) and among the various age groups, although there was a trend toward a lower incidence of adverse events among patients in the pediatric and elderly population as compared with subjects in the 18±60 year age range (P < 0.05). There was a significant nonlinear trend toward an increased incidence of adverse events among patients given ProHance doses greater than 0.1 mmol/kg. This was caused in part by the inclusion in this analysis of a normal volunteer study in which each of the ten patients studied reported at least one adverse event after a dose of 0.3 mmol/kg gadoteridol. The increase in adverse events at the higher dose levels can be attributed in the main to procedure-related volume effects such as increased injection site reactions. The incidence of the most commonly reported reactions (nausea and headache) was similar among subjects given the 0.1 and 0.3 mmol/kg doses.

Since gadoteridol was first approved for marketing in the United States in 1992 well over one million doses have been administered worldwide. This report confirms the excellent safety profile of this agent in healthy subjects as well as patients with a variety of known or suspected pathologies.

Conclusions As a class, the extracellular gadolinium agents have been administered safely to over 10 million patients.

A single exposure may have resulted in adverse events in more than one category, therefore percentages do not add up to 100 % c In three of these four patients the investigator felt these categories were ªnot applicableº

Acknowledgement. The authors wish to acknowledge the expert advice of Lukas Makris, PhD, without whose assistance this analysis would not have been possible.

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