For CNS imaging
in term neonates1

ProHance is the
fastest-growing
GBCA in the U.S.2

Minimal Gd Retention

 

In brain and body tissues3-8,*

Safety Profile

 

Established safety profile in over 40 million patients2

Proven Efficacy

 

Performances of Gadavist and ProHance for visualization parameters are similar in MRI of the CNS11,12

*Based on animal studies and small scale clinical investigations. The clinical significance of Gd retention is unknown. Generalizability of animal model results to humans has not been established.

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In this paper, the Barrow Neurological Institute shares:
• Their rationale for switching to a macrocyclic GBCA
• How differences between macrocyclics factored into their choice of agent
• Outcomes and experience with ProHance to date



Gadolinium retention is seen following the administration of any of the GBCAs, but there are differences among linear and macrocyclic agents 3,4,13-15

Levels of retained Gd following macrocyclic GBCAs are very low, showing some degree of variability.

Although the American College of Radiology (ACR) and the Food and Drug Administration (FDA) agree that there are no known adverse clinical consequences associated with Gd retention in the brain based on the available data,16,17 some practitioners may have concerns in light of the litigation environment surrounding GBCAs.

Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at four weeks has been established. Gadolinium retention equalizes over time.

Tissue sampling studies using inductively coupled plasma mass spectrometry (ICP-MS) provide superior sensitivity for quantification of gadolinium than studies utilizing MRI signal intensity analysis15

Cerebellum

Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at four weeks has been established. Gadolinium retention equalizes over time.

Adapted from Bussi et al. Insights into Imaging. 2020. Gd = gadolinium; LOQ = limit of quantitation. Gadovist is the brand name in Europe for Gadavist® (Gadobutrol).

Cerebrum

Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at four weeks has been established. Gadolinium retention equalizes over time.

Adapted from Bussi et al. Insights into Imaging. 2020. Gd = gadolinium; LOQ = limit of quantitation. Gadovist is the brand name in Europe for Gadavist® (Gadobutrol).

Liver

Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at four weeks has been established. Gadolinium retention equalizes over time.

Adapted from Bussi et al. Insights into Imaging. 2020. Gd = gadolinium; LOQ = limit of quantitation. Gadovist is the brand name in Europe for Gadavist® (Gadobutrol).

Kidneys

Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at four weeks has been established. Gadolinium retention equalizes over time.

Adapted from Bussi et al. Insights into Imaging. 2020. Gd = gadolinium; LOQ = limit of quantitation. Gadovist is the brand name in Europe for Gadavist® (Gadobutrol).

Skin

Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at four weeks has been established. Gadolinium retention equalizes over time.

Adapted from Bussi et al. Insights into Imaging. 2020. Gd = gadolinium; LOQ = limit of quantitation. Gadovist is the brand name in Europe for Gadavist® (Gadobutrol).

Femur

Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at four weeks has been established. Gadolinium retention equalizes over time.

Adapted from Bussi et al. Insights into Imaging. 2020. Gd = gadolinium; LOQ = limit of quantitation. Gadovist is the brand name in Europe for Gadavist® (Gadobutrol).

Data from the Bussi studies in rats using ICP-MS consistently indicate…

ProHance demonstrated low Gd retention in body organs in rat studies.3,4

Cerebellum

P

Cerebrum

P

Liver

P

Kidneys

P

Skin

P

Femur

P
Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at four weeks has been established. Gadolinium retention equalizes over time.

Data from the Bussi study, using ICP-MS, indicate…

ProHance demonstrated low Gd retention in body organs in rat study.3

Human data from a small-scale tissue sampling study using ICP-MS indicate that…

ProHance administration results in low residual gadolinium in the brain.5

Adapted from Murata N, et al. Invest Radiol. 2016
Gadovist is the brand name in Europe for Gadavist® (gadobutrol).

Data from extensive animal studies in rats using ICP-MS indicate…

Fast elimination of ProHance in the first 5 weeks after last injection.6,18

Generalizability of animal model results to humans has not been established. Neither the clinical significance of Gd retention in tissues nor the significance of Gd retention differences at five weeks has been established. Gadolinium retention equalizes over time.
Adapted from Jost G, et al. Radiology. 2018

Safety Profile: Prospective data from two observational studies show 0 serious AEs and AE rates as low as 0.16%9,10

6,163 patients evaluated, 0 serious AEs9
Prospective multicenter data from 6,163 patients who received ProHance demonstrate a 0.16% AE rate, with no serious AEs reported.

28,078 patients and an AE rate of 0.66%10
In a prospective observational study consisting of 28,078 patients exposed to ProHance, there was an overall adverse reaction rate of 0.66%.

Safe for use in children, including term neonates1
Indicated for use in MRI in children, including term neonates, to visualize lesions with abnormal vascularity in the brain (intracranial lesions), spine, and associated tissue1

ProHance: The only GBCA with the option for a cumulative dose up to 3 times standard 0.1 mmol/kg dose in adult patients.1

ProHance is not approved for triple dose in children.

Proven Efficacy: Performances of Gadavist and ProHance for visualization parameters are similar11,12

Detection and characterization of CNS lesions with ProHance (Gadoteridol) was non-significantly different when compared to Gadavist (gadobutrol)…12

Minimal differences in relaxivity between ProHance and Gadavist do not demonstrate clinical differences in routine neuroradiological applications of CNS MRI.11,12

61-year-old man with brain metastases from primary lung cancer. Two lesions clearly seen in both exams show no differences in contrast enhancement or in the morphology of lesions.12

51-year-old woman with glioblastoma multiforme. Rim- enhancing mass in right thalamus with extension into the posterior interhemispheric region is clearly seen in both examinations. No differences in contrast enhancement or in the morphology of lesions are apparent.12

Adapted from Maravilla KR, et al. AJNR Am J Neuroradiol. 2015
These are representative images from reference studies; individual results may vary.

The TRUTH study showed no significant difference by any reader for any of the 5 endpoints:12
• Global diagnostic preference
• Lesion border delineation
• Definition of disease extent
• Visualization of lesion internal morphology
• Lesion contrast enhancement

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Gd = Gadolinium.
GBCA = Gadolinium-based contrast agent.
ICP-MS = Inductively coupled plasma mass spectrometry.
References:

  1. ProHance® (Gadoteridol) injection full Prescribing Information and Patient Medication Guide. Monroe Twp., NJ: Bracco Diagnostics Inc.; December 2020.
  2. Data on file. Bracco Diagnostics Inc. based on IQVIA DDD: January 2021.
  3. Bussi S, Coppo A, Celeste R, et al. Macrocyclic MR contrast agents: evaluation of multiple-organ gadolinium retention in healthy rats. Insights Imaging. 2020;11(11):doi.org/10.1186/s13244-019-0824-5.
  4. Bussi S, Coppo A, Botteron C, et al. Differences in gadolinium retention after repeated injections of macrocyclic MR contrast agents to rats. J Magn Reson Imaging. 2018;47(3):746-752. (Macrocyclic MR contrast agents administered to rats over a 5 week period and Gd retention tested 4 weeks after last administration.)
  5. Murata N, Gonzalez-Cuyar LF, Murata K, et al. Macrocyclic and other non-group 1 gadolinium contrast agents deposit low levels of gadolinium in brain and bone tissue: preliminary results from 9 patients with normal renal function. Invest Radiol. 2016;51(7):447-453. (Tissue samples were collected from 9 decedents undergoing autopsy who had contrast-enhanced magnetic resonance imaging (MRI) with only single agent exposure to a non-Group 1 Gd-based contrast agent.)
  6. Jost G, Frenzel T, Boyken J, Lohrke J, Nischwitz V, Pietsch H. Long-term excretion of gadolinium-based contrast agents: linear versus macrocyclic agents in an experimental rat model. Radiology. 2018;13:180135. (Linear and macrocyclic MR contrast agents administered to rats over a 2 week period and Gd retention tested 5, 26 and 52 weeks after administration.)
  7. Frenzel T, Ulbrich HF, Pietsch H. The macrocyclic gadolinium-based contrast agents gadobutrol and gadoteridol show similar elimination kinetics from the brain after repeated intravenous injections in rabbits. Invest Radiol. 2020;10.1097/RLI.0000000000000749.
  8. Radbruch A, Richter H, Fingerhut S, et al. Gadolinium deposition in the brain in a large animal model: comparison of linear and macrocyclic gadolinium-based contrast agents. Invest Radiol. 2019;54(9):531-536.
  9. Cho SB, lee Al, Chang HW, et al. Prospective multicenter study of the safety of gadoteridol in 6163 patients. J Magn Reson Imaging. 2020;doi:10.1002/jmri.26940.
  10. Morgan DE, Spann JS, Lockhart ME, Winningham B, Bolus DN. Assessment of adverse reaction rates during gadoteridol-enhanced MR imaging in 28,078 patients. Radiology. 2011;259:109–116.
  11. Gadavist® (gadobutrol) injection full Prescribing Information and Patient Medication Guide. Whippany, NJ: Bayer HealthCare Pharmaceuticals Inc.; July 2019.
  12. Maravilla KR, Smith MP, Vymazal J, et al. Are there differences between macrocyclic gadolinium contrast agents for brain tumor imaging? Results of a multicenter intraindividual crossover comparison of gadobutrol with gadoteridol (the TRUTH study). AJNR Am J Neuroradiol. 2015;36(1):14-23.
  13. McDonald RJ, McDonald JS, Dai D, et al. Comparison of gadolinium concentrations within multiple rat organs after intravenous administration of linear versus macrocyclic gadolinium chelates. Radiology. 2017; 285(2):536-545. (Linear and macrocyclic MR contrast agents administered to rats over a 26 day period and Gd retention tested 7 days after final administration.)
  14. Guo BJ, Yang ZL, Zhang LJ. Gadolinium deposition in brain: current scientific evidence and future perspectives. Front Mol Neurosci. 2018;11:335. (Review article.)
  15. McDonald RJ, Levine D, Weinreb J, et al. Gadolinium retention: a research roadmap from the 2018 NIH/ACR/RSNA workshop on gadolinium chelates. Radiology. 2018;289(2):517-534.
  16. FDA Drug Safety Communication: FDA warns that gadolinium-based contrast agents (GBCAs) are retained in the body; requires new class warnings. FDA website. https://www.fda.gov/drugs/drug-safety-and-availability/fda-drug-safety-communication-fda-warns-gadolinium-based-contrast-agents-gbcas-are-retained-body. December 19, 2017. Accessed January 6, 2020.
  17. ACR Committee on Drugs and Contrast Media. ACR Manual on Contrast Media. 2021 edition.
  18. Bussi S, Coppo A, Bonafè R, Rossi S, Colombo Serra S, Penard L, Kirchin MA, Maisano F, Tedoldi F. Gadolinium clearance in the first 5 weeks after repeated intravenous administration of gadoteridol, gadoterate meglumine, and gadobutrol to rats. J Magn Reson Imaging. 2021 May 11. doi: 10.1002/jmri.27693. Epub ahead of print.

ProHance® (Gadoteridol) Injection, 279.3 mg/mL
and
ProHance® MultipackTM (Gadoteridol) Injection, 279.3 mg/mL

Indications and Usage:

CENTRAL NERVOUS SYSTEM
ProHance® (Gadoteridol) Injection, 279.3 mg/mL is indicated for use in MRI in adults and pediatric patients including term neonates to visualize lesions with disrupted blood brain barrier and/or abnormal vascularity in the brain (intracranial lesions), spine and associated tissues.

EXTRACRANIAL/EXTRASPINAL HEAD AND NECK
ProHance (Gadoteridol) Injection, 279.3 mg/mL is indicated for use in MRI in adults to visualize lesions in the head and neck.

IMPORTANT SAFETY INFORMATION:

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS

Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs.

  • The risk for NSF appears highest among patients with:
    • chronic, severe kidney disease (GFR <30 mL/min/1.73m2), or
    • acute kidney injury.
  • Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (e.g. age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.
  • For patients at highest risk for NSF, do not exceed the recommended ProHance dose and allow a sufficient period of time for elimination of the drug from the body prior to re-administration.

 

CONTRAINDICATIONS
Contraindicated in patients with known allergic or hypersensitivity reactions to ProHance.

WARNINGS AND PRECAUTIONS
Nephrogenic Systemic Fibrosis: NSF has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase risk.
Hypersensitivity Reactions: Anaphylactic and anaphylactoid reactions have been reported, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of administration and resolved with prompt emergency treatment. Prior to ProHance administration, ensure the availability of trained personnel and medications to treat hypersensitivity reactions. Consider these risks, especially in patients with a history of hypersensitivity reactions or a history of asthma or other allergic disorders.
Gadolinium Retention: Gadolinium is retained for months or years in several organs. The highest concentrations have been identified in the bone, followed by brain, skin, kidney, liver, and spleen. Linear GBCAs cause more retention than macrocyclic GBCAs. Consequences of gadolinium retention in the brain have not been established, but they have been established in the skin and other organs in patients with impaired renal function.
Acute Kidney Injury: In patients with chronically reduced renal function, acute kidney injury requiring dialysis has occurred with the use of GBCAs. The risk of acute kidney injury may increase with increasing dose of the contrast agent; administer the lowest dose necessary for adequate imaging.

ADVERSE REACTIONS
The most commonly reported adverse reactions are nausea and taste perversion with an incidence ≥ 0.9%.

USE IN SPECIFIC POPULATIONS
Pregnancy: GBCAs cross the human placenta and result in fetal exposure and gadolinium retention. Use only if imaging is essential during pregnancy and cannot be delayed.
Lactation: There are no data on the presence in human milk, the effects on the breastfed infant, or the effects on milk production. However, published lactation data on other GBCAs indicate that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk.
Pediatric Use: The safety and effectiveness of ProHance have been established for use with MRI to visualize lesions with abnormal blood brain barrier or abnormal vascularity of the brain, spine, and associated tissues in pediatric patients from birth, including term neonates, to 17 years of age. Adverse reactions in pediatric patients were similar to those reported in adults. No case of NSF associated with ProHance or any other GBCA has been identified in pediatric patients ages 6 years and younger.

Please see full Prescribing Information and Patient Medication Guide for additional important safety information for/regarding ProHance (Gadoteridol) Injection, 279.3 mg/mL at https://www.braccoimaging.com/us-en/products/magnetic-resonance-imaging/prohance

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

ProHance is manufactured for Bracco Diagnostics Inc. by BIPSO GmbH – 78224 Singen (Germany).

ProHance is a registered trademark of Bracco Diagnostics Inc.

ProHance Multipack is a trademark of Bracco Diagnostics Inc.

All other trademarks and registered trademarks are the property of their respective owners.

Bracco Diagnostics Inc.
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Toll Free: 1-877-272-2269 (U.S. only) Fax: 609-514-2446

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