en en fi en en en en en fr en en en en en en en en en en en en en en en en en en en en en he en en en en en en en en en en en ro it en eu en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en en it en en en en en en en en en en en
Applied Radiology recently spoke with Tom McLaughlin, Guerbet’s Vice President for North America, about the company’s dedication to imaging and development of innovative solutions to support radiology. The discussion focused in particular on DOTAREM® (gadoterate meglumine) Injection, the company’s flagship MRI contrast agent that provided entry into the U.S. imaging market. This article is based on that discussion.
Since its release in 1989, DOTAREM® (gadoterate meglumine) Injection has been a leading MR contrast agent in Europe, Asia, Africa, the Middle East, and South America. Dotarem received U.S. Food and Drug Administration (FDA) approval in 2013, becoming the first macrocyclic, ionic gadolinium-based contrast agent (GBCA) in the United States. In just seven years, it has become the No. 2 MR contrast agent in the US and is currently No. 1 in the world, with more than 100 million doses delivered in 70 countries.
“We are making great strides in the U.S. with our flagship product, Dotarem. Dotarem is the fuel that keeps us running and fuels our commitment to radiologists in the MR suite,” says Tom McLaughlin, Guerbet’s Vice President, North America.
Stability Considerations in MR Contrast Selection
Dotarem has gained a significant share of the U.S. market, despite continuing volatility in the market for such agents. Dotarem continues to be a leading choice of radiologists and technicians. No unconfounded cases of NSF1 have been reported with Dotarem. In addition, Dotarem’s ionic macrocyclic structure provides high molecular stability to minimize the risk of gadolinium release from the GBCA molecule.2
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 reviewed.3
“There's no doubt that stability of MR contrast agents is a big subject for radiologists today, because of all the talk about gadolinium deposition,” says McLaughlin. “There's no doubt that we have the highest kinetic and thermodynamic stability for our macrocyclic ionic molecule, Dotarem.” Importantly, he notes that the FDA has found no direct link between gadolinium retention and adverse health effects in patients with normal kidney function, and that the benefit of any approved GBCA continues to outweigh any potential risk.
MR technologists are also embracing the delivery of Dotarem in pre-filled plastic syringes, providing for quick setup of the MR injector and reducing the risk of contamination.1 In April 2020, Guerbet announced it received FDA approval to manufacture Dotarem injection at its Raleigh, North Carolina facility. Until late 2019, Dotarem was manufactured exclusively outside of the United States. Guerbet intends to produce Dotarem within the United States for US-based customers, in alignment with Guerbet’s broader vision to supply US-manufactured products to US customers.
The Raleigh facility is manufacturing Dotarem in both vials and plastic syringes. The plastic syringes feature a new pushrod that is designed to make hand injections more ergonomic, and plastic pre-filled syringes reduce patient risks including the chance of contamination as compared to bulk fill containers.2 The new, more durable outer packaging allows for both improved convenience and workflow efficiency in the radiology suite.
Guerbet’s Contrast & Care® injection management solution, meanwhile, enables clinicians to capture and transfer each study’s contrast data to the patient’s electronic medical record (EMR), as well as to archive, review, and share it with other providers as necessary. This comprehensive data includes the type and amount of contrast media loaded and injected, as well as the agent’s NDC number, lot number, and fill size. Contrast & Care also can track adverse events, injector activity, eGFR information, and other pre-exam alerts, such as patient allergies. The solution’s patient worklist and data-recall capabilities permit risk checking and review of injection protocols for each patient, a critical aspect of reducing risk to patients with renal function concerns.
“With a quick scan of the barcode, we can have all of that information follow the patient in their EMR, which is then available for future reference,” McLaughlin says. “Contrast & Care is a very, very vital piece for the technologist, so that they can get the information into the EHR and make the reference for kidney function for the patient.”
The Future with AI
McLaughlin also envisions a significant role for artificial intelligence (AI) in the future of medical imaging. He says Guerbet is committed to partnering with radiologists, technologists, and administrators to deliver the AI tools they will increasingly need to perform their job effectively.
“AI is a big buzz word right now within the radiology community. As we move forward, we want to take advantage of technology to enhance the radiologist’s workflow and the patient experience, and also to make life a little bit easier for radiologists, technologists, and administrators with digital solutions that include AI,” McLaughlin explains.
One example is Guerbet’s IBM Watson Imaging Patient Synopsis, a radiologist-trained AI tool that aims to extract patient information from the EMR and summarize that data in a dashboard tailored to help inform diagnostic decisions. The AI engine searches for all relevant data from unstructured reports in a patient’s EMR and assembles that data to provide a more holistic view of the patient. Clinicians no longer have to click laboriously through a patient’s entire EMR – the system surfaces relevant data so they can make better decisions faster and more efficiently.
Changing Environment in Radiology
Guerbet’s commitment to the radiology community is more important than ever, as the field is being challenged to address changing needs due to the COVID-19 outbreak. “We know how important our products are for this industry, and we’re making sure that we’re doing everything we can to keep our CT & MR injectors up and running,” McLaughlin says, noting that Guerbet is taking extra precautions to protect the safety of their field service engineers as they visit customer sites.
“At Guerbet, it's very important that we are invested in the radiology department,” McLaughlin concludes. “Guerbet is dedicated to radiology, and we want to continue bringing solutions that help innovate and improve the field.”
1. Dotarem [package insert]. Princeton, NJ: Guerbet LLC; Aug 2018.
2. Frenzel T et al. Stability of gadolinium-based magnetic resonance imaging contrast agents in human serum at 37°C. Invest Radiol. 2008; 43:817-828.
3. Behzadi AH et al. Radiology. 2018; 286:471-482.
4. Buerke B. et al., Microbiologic Contamination and Time Efficiency of Use of Automatic MDCT Injectors With Prefilled Syringes: Results of a Clinical Investigation, AJR: 194, February 2010, 299:303.
5. Buerke B. et al., Microbiologic Contamination and Time Efficiency of Use of Automatic MDCT Injectors With Prefilled Syringes: Results of a Clinical Investigation, AJR: 194, February 2010, 299:303.
Dotarem® Important Safety Information
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.
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.
History of clinically important hypersensitivity reactions to DOTAREM.
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.
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.
Editor’s note: Guerbet is a French pharmaceutical and medical device group 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.