Delivering Stability with Macrocyclic Gadolinium Based Contrast Agents

Published Date: December 18, 2020

By McKenna Bryant

Dotarem® (gadoterate meglumine) Injection Important Safety Information¹

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. A void 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 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/l.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, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.
For patients at highest risk for NSF, do not exceed the recommended DOTAREM® dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration.

Additional important safety information below.

Gadolinium-based contrast agents (GBCAs) are generally considered safe and effective for their FDA-approved indications. However, in recent years, two factors impacting the GBCA market are nephrogenic systemic fibrosis (NSF) and reports of gadolinium deposition in the brain, bones, and other tissues.

These considerations often drive radiologists to choose a more stable, macrocyclic GBCAs, such as Dotarem® (gadoterate meglumine)¹. “The role for using macrocyclic agents is pretty clear. There's a big need for MR studies with contrast, so we want to choose agents that have high molecular stability and a proven safety profile,” says Dr. Ari Goldberg, MD, an associate professor of radiology, medical director for Body Imaging, and medical director for MRI at Loyola University Medical Center in Chicago.

Macrocyclic agents like Dotarem® are particularly useful in renally compromised patients who have known renal disease and are at risk for either the potential worsening of their renal conditions or the development of NSF. Some macrocyclic agents like Dotarem are also approved for pediatric use. A 2016 survey of pediatric radiology departments found that 58% (15 of 26) of respondents switched their GBCA for reasons due to the growing concerns of linear GBCAs.² “Our practice is focusing on macrocyclic agents, and it definitely plays a role in pediatric imaging,” says Donna Roberts, MD, a fellowship trained neuroradiologist and professor of radiology at the Medical University of South Carolina.

Since its release in 1989, Dotarem® has been a leading MR Contrast agent in Europe, Asia, Africa, the Middle East, and South America. Dotarem® was approved by the U.S. Food and Drug Administration (FDA) in 2013 as the first macrocyclic, ionic GBCA in the United States. In just seven years, it has become the No. 2 MR contrast agent in the U.S. and is currently No. 1 in the world, with more than 100 million doses administered in 70 countries.³

Dotarem® has gained a significant share of the U.S. market and continues to be a leading choice of radiologists and technicians, with no unconfounded cases of NSF¹; reported to date. In addition, Dotarem’s ionic, macrocyclic structure provides high molecular stability to minimize the risk of gadolinium release from the GBCA molecule.⁴ A systematic review and meta-analysis of nine studies covering more than 716,000 GBCA administrations found that Dotarem®’s total rate of adverse drug reactions is among the lowest of the macrocyclic agents.⁵

Understanding the Importance of GBCA Stability

There are two different types of GBCA chelates. One type, called a linear agent, partially wraps around the gadolinium molecule. Another type, called a macrocyclic agent, forms a cage around the gadolinium to tightly bind the molecule.⁴ Macrocyclic agents are more stable than the linear agents, which is very important to take into account when we're determining which gadolinium-based contrast agent to use,” says Dr. Roberts.

She also notes that NSF in children is rare. According to the latest ACR Manual on contrast media, as of 2012 approximately 23 cases of NSF were reported. All patients were 6 years of age or older.⁶ She states, “The majority of single agent cases of NSF has occurred in linear agents, which is why we're concerned about the choices between macrocyclic versus linear agents in our pediatric patients.”

Choosing a Macrocyclic Agent

Radiologists must balance patient safety, agent stability and diagnostic image quality when choosing a MR contrast agent. "Safety is most important when considering which agent to use. We need to consider potential consequences, such as the potential for NSF when choosing which agent to use in our patients,” says Dr. Roberts. “This is particularly concerning when imaging pediatric patients in the neonatal development period, when renal function is immature.”

Dr. Goldberg’s practice is part of a large healthcare system comprising more than 100 hospitals. The healthcare system formed a subcommittee of the clinical leadership group, including radiologists, nephrologists, pharmacists, legal advocates, and radiological technicians, to review contrast agent. “The process by which we determined to use Dotarem® was based on considerable analysis of its safety and stability. But it also had to meet a non-inferiority metric for imaging. We had to satisfy for ourselves that the actual quality in terms of lesion conspicuity in clinical imaging was not going to be compromised,” he says.

The process included a data review of Dotarem®’s safety profile, as well as its impact on image quality, before concluding it was the right MR agent choice. “We chose Dotarem® because of its wealth of clinical, population-based information that demonstrates its relative benefits in terms of safety profile.”

GBCA Stability an Important Consideration for Vulnerable Patients

In the context of vulnerable patient populations, GBCA stability is an important selection factor, and this is where Dotarem® stands out.^5,7 Dr. Goldberg’s own research aligns with this assessment. He is in the process of releasing a study of estimated glomerular filtration rates (eGFRs) and NSF to evaluate the potential acute nephrotoxicity of Dotarem® in patients with very low eGFRs (under 30), indicating advanced renal disease. GFR is a test that checks how well the kidneys are working by estimating how much blood passes through the glomeruli – tiny filters in the kidneys – each minute. This study followed more than 300 patients: control subjects who didn’t receive Dotarem® injections, and subjects who did receive Dotarem®. The eGFRs of each subject were recorded to determine if there were any nephrotoxicity effects that occurred in renally compromised patients.

“Our study demonstrated that there’s no statistically significant risk of true nephrotoxicity when using Dotarem®, even in patients with an eGFR less than 30,” he says of his soon-to-be-published study. “There's no data to suggest that there's any nephrotoxicity associated with Dotarem®, even in a vulnerable patient population."

Dotarem® Important Safety Information¹

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

The risk for NSF appears highest among patients with:
⇒ Chronic, severe kidney disease (GFR < 30 mL/min/l.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, diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.
For patients at highest risk for NSF, do not exceed the recommended DOTAREM® dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration.

Indications and Usage
DOTAREM® (gadoterate meglumine) injection is a prescription gadolinium-based contrast agent indicated for intravenous use with magnetic resonance imaging (MRI) in brain (intracranial), spine and associated tissues in adult and pediatric patients (including term neonates) to detect and visualize areas with disruption of the blood brain barrier (BBB) and/or abnormal vascularity.

Contraindications
History of clinically important hypersensitivity reactions to DOTAREM®.

Warnings and Precautions

Hypersensitivity Reactions: Anaphylactic and anaphylactoid reactions have been reported with DOTAREM®, involving cardiovascular, respiratory, and/or cutaneous manifestations. Some patients experienced circulatory collapse and died. In most cases, initial symptoms occurred within minutes of DOTAREM® administration and resolved with prompt emergency treatment.
Before DOTAREM® administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and/or allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to DOTAREM®.
Administer DOTAREM® only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.
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. The duration of retention also varies by tissue, and is longest in bone. Linear GBCAs cause more retention than macrocyclic GBCAs.
Consequences of gadolinium retention in the brain have not been established. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention.
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.
Extravasation and Injection Site Reactions: Ensure catheter and venous patency before the injection of DOTAREM®. Extravasation into tissues during DOTAREM® administration may result in tissue irritation.

Adverse Reactions

The most common adverse reactions associated with DOTAREM® in clinical trials were nausea, headache, injection site pain, injection site coldness and rash.
Serious adverse reactions in the Postmarketing experience have been reported with DOTAREM®. These serious adverse reactions include but are not limited to: arrhythmia, cardiac arrest, respiratory arrest, pharyngeal edema, laryngospasm, bronchospasm, coma and convulsion.

Use in Specific Populations

Pregnancy: GBCAs cross the human placenta and result in fetal exposure and gadolinium retention. The human data on the association between GBCAs and adverse fetal outcomes are limited and inconclusive. Advise pregnant women of the potential risk of fetal exposure to GBCAs.
Lactation: There are no data on the presence of gadoterate 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 efficacy of DOTAREM® at a single dose of 0.1 mmol/kg has been established in pediatric patients from birth (term neonates ~ 37 weeks gestational age) to 17 years of age based on clinical data. The safety of DOTAREM® has not been established in preterm neonates. No cases of NSF associated with DOTAREM® or any other GBCA have been identified in pediatric patients age 6 years and younger.

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.

Please see the full Prescribing Information, including the patient Medication Guide, for additional important safety information. For more information, visit https://www.guerbet.com/products-solutions/

References

Dotarem [package insert]. Princeton, NJ: Guerbet LLC; October 2019.
Use of gadolinium-based contrast agents in pediatric radiology departments: A 2016 survey. May 2017. https://appliedradiology.com/articles/use-of-gadolinium-based-contrast-agents-in-pediatric-radiology-departments-a-2016-survey.
Data on File. Guerbet LLC based on through Q1 2020.
Frenzel T, Lengsfeld P, Schirmer H, Hütter J, Weinmann HJ. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37 degrees C. Invest Radiol. 2008 Dec;43(12):817-28. doi: 10.1097/RLI.0b013e3181852171. PMID: 19002053.
Behzadi AH, Zhao Y, Farooq Z, Prince MR. Immediate Allergic Reactions to Gadolinium-based Contrast Agents: A Systematic Review and Meta-Analysis. Radiology. 2018 Feb;286(2):471-482. doi: 10.1148/radiol.2017162740^.Epub 2017 Aug 25. Erratum in: Radiology. 2018 Feb;286(2):731. PMID: 28846495.
ACR Manual on Contrast Media 2020, ACR Committee on Drugs and Contrast Media. https://www.acr.org/-/media/ACR/Files/Clinical-Resources/Contrast_Media.pdf
Perazella MA. Current status of gadolinium toxicity in patients with kidney disease. Clin J Am Soc Nephrol. 2009 Feb;4(2):461-9. doi: 10.2215/CJN.06011108. Erratum in: Clin J Am Soc Nephrol. 2009 Apr;4(4):866. PMID: 19201920.

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Editor’s Note:
Guerbet LLC., the US affiliate of Guerbet, is a pharmaceutical and medical device company that offers a comprehensive range of specialized solutions for diagnostic and interventional radiology. The company’s portfolio includes products, services, and digital software solutions for MRI, CT, and interventional radiology (including the cath lab and women’s health). Driven by its commitment to advance radiology, Guerbet has designed a range of interconnected contrast imaging solutions to enhance decision making at all points of a patient’s journey – diagnosis, treatment, documentation, and follow-up – so that clinicians can focus on what matters most: quickly and efficiently improving the patient experience.

Applied Radiology spoke with Ari Goldberg, MD, associate professor of radiology, medical director for Body Imaging, and medical director for MRI at Loyola University Medical Center and Donna Roberts, MD, a fellowship trained neuroradiologist and professor of radiology at the Medical University of South Carolina, about their experiences with macrocyclic contrast agents. This article is based on that conversation.