Pharmacokinetics and Safety of Macrocyclic Gadobutrol in Children Aged Younger Than 2 Years Including Term Newborns in Comparison to Older Populations

Kunze, Christian; Mentzel, Hans Joachim; Krishnamurthy, Rajesh; Fleck, Robert; Stenzel, Martin; Bhargava, Ravi; Burrowes, Delilah; Sutter, Gerd; Schultze-Mosgau, Marcus; Santiuste, Marta; Hahn, Gabriele

doi:10.1097/rli.0000000000000204

Cited by 24 publications

(39 citation statements)

References 27 publications

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“…Clinical and observational studies on a range of indications in adults and children have demonstrated gadobutrol to be efficacious with a favourable safety and tolerability profile [13–15]. At the request of the European Medicines Agency (EMA), a prospective, multicentre, non-interventional study, GARDIAN (Gadovist® in Routine Diagnostic MRI – Administration in Non-selected Patients), was initiated to evaluate the acute safety and tolerability of gadobutrol use in approved indications in a large patient population in routine practice, including the age group 2 to 7 years as well as patients with renal impairment or cardiac disease and patients considered at risk for contrast media (CM) reactions.…”

Section: Introductionmentioning

confidence: 99%

Safety of gadobutrol in over 23,000 patients: the GARDIAN study, a global multicentre, prospective, non-interventional study

Prince

Lee

et al. 2016

Eur Radiol

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ObjectivesTo investigate the safety and tolerability of gadobutrol at the recommended dose in patients requiring contrast-enhanced magnetic resonance imaging/angiography (MRI/MRA) in the routine setting.MethodsGARDIAN prospectively enrolled 23,708 patients undergoing routine gadobutrol-enhanced MRI/MRA for approved indications at 272 study centres in Europe, Asia, North America, and Africa and monitored for adverse events.ResultsMedian gadobutrol dose was 0.11 mmol/kg body weight. The overall incidence of adverse drug reactions (ADRs) was 0.7 % (n = 170 patients), with similar incidences in patients with renal impairment or cardiac disease, from different geographic regions and in different gadobutrol dose groups. Patients at risk for contrast media reaction had an ADR incidence of 2.5 %. Five patients (0.02 %) experienced serious adverse events, four were drug-related. One patient experienced a fatal anaphylactoid shock, assessed to be related to injection of gadobutrol. The contrast quality of gadobutrol-enhanced images was rated by treating physicians as good or excellent in 97 % cases, with similar ratings in all patient subgroups and indications.ConclusionsThe GARDIAN study shows that gadobutrol at the recommended dose is well tolerated across a large, diverse patient population.Key points• Gadobutrol at recommended dose shows low rates of adverse drug reactions • Gadobutrol demonstrates a uniform safety profile across diverse patient groups • Gadobutrol provides excellent contrast quality in routine practice

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Section: Introductionmentioning

confidence: 99%

Safety of gadobutrol in over 23,000 patients: the GARDIAN study, a global multicentre, prospective, non-interventional study

Prince

Lee

et al. 2016

Eur Radiol

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“…These compounds have been used for over 25 years with an excellent safety profile other than the association with nephrogenic systemic fibrosis in those with renal impairment (2,3). Several investigations (4)(5)(6)(7) into the use of these compounds in children have shown that they are safe for use in MR examinations, and have fewer adverse outcomes in children than in adults.…”

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confidence: 99%

“…In adults and children, the majority of studies show no increased signal intensity with multiple doses of macrocyclic GBCAs. Gadobutrol (Gd-DO3A-butrol, Gadovist, Gadavist; Bayer Pharma, Leverkusen, Germany) is a secondgeneration macrocyclic GBCA used to enhance tissue contrast at MRI for a range of approved indications in adults and children of all ages (29). In December 2014, the U.S. Food and Drug Administration approved gadobutrol for use at MRI of the central nervous system in children younger than 2 years, and it is approved in many other countries for whole-body MRI in this age group (7). The American College of Radiology, European Medicines Agency, and the European Society of Urogenital Radiology placed gadobutrol in the lowest risk category for development of nephrogenic systemic fibrosis (11)(12)(13).…”

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confidence: 99%

Multiple Administrations of Gadobutrol in the Pediatric Brain: No Change in T1 Signal at MRI

et al. 2018

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Purpose To determine whether multiple doses of gadobutrol increase the T1 signal intensity in the brains of children. Materials and Methods This retrospective imaging study evaluated 91 children (median age, 5.4 years; age range, 0-17 years) with brain tumors who underwent five or more MR brain examinations at a single institution. A subgroup of 46 patients received five or more administrations of gadobutrol (0.1 mmol/kg) and underwent follow-up MRI. T1 signal intensity in the globus pallidus and dentate nucleus was measured at the first to sixth unenhanced MR brain examination in these children. Globus pallidus-to-corpus callosum and dentate nucleus-to-corpus callosum signal intensity ratios were analyzed by linear mixed-effect analysis. Subgroup analysis was performed for six children who underwent 14 or more administrations of gadobutrol. Results The globus pallidus-to-corpus callosum ratio increased with patient age (absolute change, 0.0052 per year; 95% confidence interval: 0.0033, 0.0071; P < .0001). There was no change in the dentate nucleus-to-corpus callosum ratio with age (P = .30). Among 46 children who received five or more doses of gadobutrol (median dose, 11 mL; range, 3.9-31 mL), there was no change in signal intensity ratio of the globus pallidus (P = .17) or dentate nucleus (P = .44). Among six children who underwent more than 14 administrations of gadobutrol (median dose, 64 mL; range, 40-91 mL) there was no change in signal intensity ratio of the globus pallidus (P = .15) or dentate nucleus (P = .50). Conclusion No increase in T1-weighted signal intensity ratio was observed in the globus pallidus or dentate nucleus after the administration of at least five doses of gadobutrol. © RSNA, 2018 Online supplemental material is available for this article.

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“…The PK profile was similar to that in older children and adults. In all, 1 of 44 patients (2.3%) experienced a drug-related AE (mild vomiting), 25 whereas in a study of 57 patients <2 years, no AE was recorded. 26 …”

Section: Safetymentioning

confidence: 85%

Gadobutrol in India—A Comprehensive Review of Safety and Efficacy

Endrikat

Anzalone

2017

Magn Reson�Insights

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Gadobutrol is a gadolinium (Gd)-based contrast agent for magnetic resonance imaging (MRI). In India, gadobutrol is approved for MRI of the central nervous system (CNS), liver, kidneys, breast and for MR angiography for patients 2 years and older. The standard dose for all age groups is 0.1 mmol/kg body weight. The safety profile has been demonstrated in 42 clinical phase 2 to 4 studies (>6800 patients), 7 observational studies, and by assessing pharmacovigilance data of 29 million applications. Furthermore, studies in children, adults, and elderly and in patients with impaired liver or kidney function did not show any increased adverse event rate. Diagnostic efficacy was demonstrated in numerous studies and various indications, such as diseases of the CNS, peripheral and supra-aortic vessels, kidneys, liver, and breast.

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Pharmacokinetics and Safety of Macrocyclic Gadobutrol in Children Aged Younger Than 2 Years Including Term Newborns in Comparison to Older Populations

Cited by 24 publications

References 27 publications

Safety of gadobutrol in over 23,000 patients: the GARDIAN study, a global multicentre, prospective, non-interventional study

Safety of gadobutrol in over 23,000 patients: the GARDIAN study, a global multicentre, prospective, non-interventional study

Multiple Administrations of Gadobutrol in the Pediatric Brain: No Change in T1 Signal at MRI

Gadobutrol in India—A Comprehensive Review of Safety and Efficacy

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