Table 8, Summary of Findings of Included Primary Clinical Studies - Macrocyclic and Linear Gadolinium Based Contrast Agents for Adults Undergoing Magnetic Resonance Imaging: A Review of Safety

Main Study Findings	Authors’ Conclusion
Gutierrez, 2015a⁶
40 patients that received gadobutrol-enhanced MRI (n = 399) experienced at least one treatment-related adverse event Two patients experienced two serious adverse events that were unrelated to gadobutrol Three patients discontinued the trial due to adverse events (allergic reactions) 38 patients that received gadoteridol-enhanced MRI (n = 393) reported at least one treatment-related adverse event One patient experienced two serious adverse events that were unrelated to gadoteridol One patient discontinued the trial due to adverse events (allergic reactions) No relevant changes to clinical laboratory parameters were observed	Gadobutrol was found to have a similar safety profile to other MRI contrast agents The findings were consistent with previous studies, with respect to safety
Gutierrez, 2015b⁵
67 patients in the study (n = 343) reported at least one adverse event, 14 of which were gadobutrol-related but not serious One patient reported a serious adverse event that was determined to be unrelated to gadobutrol No deaths or discontinuations were reported No significant changes in vital signs, clinical laboratory values or hematological parameters were reported	Gadobutrol has a very good safety profile The findings are consistent with previous studies, with respect to safety
Kuwatsuru, 2015⁴
13 patients that received gadobutrol-enhanced MRI (n = 178) experienced 12 mild treatment-emergent adverse events Seven patients experienced seven drug-related treatment-emergent adverse events One patient experienced one severe treatmentemergent adverse event, which resolved after 15 minutes 16 patients that received gadopentetate dimeglumineenhanced MRI (n = 185) experienced 13 mild treatmentemergent adverse events Three patients experienced seven drug-related treatment-emergent adverse events When compared to the baseline values, there were no significant changes in clinical laboratory values, vital signs or physical examinations up to 24 hours after injection No serious adverse events, deaths or discontinuations were reported for gadobutrol or gadopentetate dimeglumine	Gadobutrol and gadopentetate are similar in safety and tolerability The observed incidence of treatment-emergent adverse events is similar to previously-reported findings
Liang, 2012¹⁸
Six out of 146 patients included in the safety analysis reported mild adverse events; one adverse event was determined to be related to the treatment Four adverse events were experienced by two patients in the gadobutrol group; four adverse events were experienced by four patients in the gadopentetate dimeglumine group	Gadobutrol and gadopentetate dimeglumine are similar with regards to safety
Naito, 2017⁷
Patients who received gadodiamide or gadopentetate dimeglumine did not experience contrast-induced nephropathy (CIN) Gadodiamide significantly increased serum cystatin-C levels from 0.74 to 0.79 (p = 0.028) In patients with stage 1 CKD who received gadodiamide, serum cystatin-C levels significantly increased from 0.69 to 0.72 (p = 0.047) In patients with stage 2 CKD who received gadodiamide, serum-creatinine levels significantly increased from 0.74 to 0.77 (p = 0.049); CCr levels significantly decreased from 80.5 to 78.5 (p = 0.039); and eGFR levels significantly decreased from 79.3 to 77.1 (p = 0.039)	Small amounts of gadolinium are safe for patients with normal or mildly-diminished renal failure Administration of gadopentetate dimeglumine has no effect on renal function Gadodiamide has slight nephrotoxicity in patients with stage 1 or 2 CKD, however, this finding is not clinically important
Semelka, 2013²⁰
No patients experienced mild (specifically emesis or hives), moderate or severe adverse events All images were rated as having “good” overall enhancement adequacy (from “poor”, “fair”, or “good”)	Adverse events were not noted amongst the 59 patients who received gadobutrol and gadobenate dimeglumine It is feasible to objectively evaluate adverse events and image quality
Tanaka, 2016²¹
19 patients (out of n = 223) reported at least one treatmentemergent adverse event, of which 6 were gadobutrolrelated The most common gadobutrol-related treatment-emergent adverse event was hot flush, experienced by 2 patients No severe adverse events or deaths were reported	Gadobutrol demonstrated good tolerability, with only 2.7% of the study population experiencing a mild adverse event
Zech, 2019¹⁹
9 patients in each group experienced at least 1 adverse event (n = 146 received gadoxetate disodium, n = 149 received gadobenate dimeglumine) 9 of 12 adverse events in the gadoxetate disodium group were probably related to the contrast administration 7 of 14 adverse events in the gadobenate dimeglumine group were possibly or probably related to the contrast administration	The safety profiles of gadoxetate disodium and gadobenate dimeglumine are similar regarding adverse events The findings are most meaningful for daily practice in examining focal liver lesions

Main Study Findings

Authors’ Conclusion

Gutierrez, 2015a⁶

40 patients that received gadobutrol-enhanced MRI (n = 399) experienced at least one treatment-related adverse event
- Two patients experienced two serious adverse events that were unrelated to gadobutrol
- Three patients discontinued the trial due to adverse events (allergic reactions)
38 patients that received gadoteridol-enhanced MRI (n = 393) reported at least one treatment-related adverse event
- One patient experienced two serious adverse events that were unrelated to gadoteridol
- One patient discontinued the trial due to adverse events (allergic reactions)
No relevant changes to clinical laboratory parameters were observed

Gadobutrol was found to have a similar safety profile to other MRI contrast agents
The findings were consistent with previous studies, with respect to safety

Gutierrez, 2015b⁵

67 patients in the study (n = 343) reported at least one adverse event, 14 of which were gadobutrol-related but not serious
One patient reported a serious adverse event that was determined to be unrelated to gadobutrol
No deaths or discontinuations were reported
No significant changes in vital signs, clinical laboratory values or hematological parameters were reported

Gadobutrol has a very good safety profile
The findings are consistent with previous studies, with respect to safety

Kuwatsuru, 2015⁴

13 patients that received gadobutrol-enhanced MRI (n = 178) experienced 12 mild treatment-emergent adverse events
- Seven patients experienced seven drug-related treatment-emergent adverse events
- One patient experienced one severe treatmentemergent adverse event, which resolved after 15 minutes
16 patients that received gadopentetate dimeglumineenhanced MRI (n = 185) experienced 13 mild treatmentemergent adverse events
- Three patients experienced seven drug-related treatment-emergent adverse events
When compared to the baseline values, there were no significant changes in clinical laboratory values, vital signs or physical examinations up to 24 hours after injection
No serious adverse events, deaths or discontinuations were reported for gadobutrol or gadopentetate dimeglumine

Gadobutrol and gadopentetate are similar in safety and tolerability
The observed incidence of treatment-emergent adverse events is similar to previously-reported findings

Liang, 2012¹⁸

Six out of 146 patients included in the safety analysis reported mild adverse events; one adverse event was determined to be related to the treatment
Four adverse events were experienced by two patients in the gadobutrol group; four adverse events were experienced by four patients in the gadopentetate dimeglumine group

Gadobutrol and gadopentetate dimeglumine are similar with regards to safety

Naito, 2017⁷

Patients who received gadodiamide or gadopentetate dimeglumine did not experience contrast-induced nephropathy (CIN)
Gadodiamide significantly increased serum cystatin-C levels from 0.74 to 0.79 (p = 0.028)
In patients with stage 1 CKD who received gadodiamide, serum cystatin-C levels significantly increased from 0.69 to 0.72 (p = 0.047)
In patients with stage 2 CKD who received gadodiamide, serum-creatinine levels significantly increased from 0.74 to 0.77 (p = 0.049); CCr levels significantly decreased from 80.5 to 78.5 (p = 0.039); and eGFR levels significantly decreased from 79.3 to 77.1 (p = 0.039)

Small amounts of gadolinium are safe for patients with normal or mildly-diminished renal failure
Administration of gadopentetate dimeglumine has no effect on renal function
Gadodiamide has slight nephrotoxicity in patients with stage 1 or 2 CKD, however, this finding is not clinically important

Semelka, 2013²⁰

No patients experienced mild (specifically emesis or hives), moderate or severe adverse events
All images were rated as having “good” overall enhancement adequacy (from “poor”, “fair”, or “good”)

Adverse events were not noted amongst the 59 patients who received gadobutrol and gadobenate dimeglumine
It is feasible to objectively evaluate adverse events and image quality

Tanaka, 2016²¹

19 patients (out of n = 223) reported at least one treatmentemergent adverse event, of which 6 were gadobutrolrelated
The most common gadobutrol-related treatment-emergent adverse event was hot flush, experienced by 2 patients
No severe adverse events or deaths were reported

Gadobutrol demonstrated good tolerability, with only 2.7% of the study population experiencing a mild adverse event

Zech, 2019¹⁹

9 patients in each group experienced at least 1 adverse event (n = 146 received gadoxetate disodium, n = 149 received gadobenate dimeglumine)
9 of 12 adverse events in the gadoxetate disodium group were probably related to the contrast administration
7 of 14 adverse events in the gadobenate dimeglumine group were possibly or probably related to the contrast administration

The safety profiles of gadoxetate disodium and gadobenate dimeglumine are similar regarding adverse events
The findings are most meaningful for daily practice in examining focal liver lesions

From: Macrocyclic and Linear Gadolinium Based Contrast Agents for Adults Undergoing Magnetic Resonance Imaging: A Review of Safety

Cover of Macrocyclic and Linear Gadolinium Based Contrast Agents for Adults Undergoing Magnetic Resonance Imaging: A Review of Safety

Macrocyclic and Linear Gadolinium Based Contrast Agents for Adults Undergoing Magnetic Resonance Imaging: A Review of Safety [Internet].

Cowling T, Frey N.

Ottawa (ON): Canadian Agency for Drugs and Technologies in Health; 2019 Jun 6.

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Table 8Summary of Findings of Included Primary Clinical Studies