Eovist
Generic Name: gadoxetate disodium
Date of Approval: July 3, 2008
Company: Bayer HealthCare Pharmaceuticals Inc.
Treatment for: Liver Magnetic Resonance Imaging
FDA Approves Eovist
Feedback for Eovist
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The U.S. Food and Drug Administration (FDA) has approved Eovist (gadoxetate disodium) Injection, a gadolinium-based contrast agent, for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease.
Eovist is a paramagnetic MRI contrast agent that combines features of both an extracellular contrast agent and a hepatocyte-specific agent. Eovist is administered via an intravenous, bolus injection and has a dual route of excretion with approximately 50 percent eliminated through the liver and 50 percent eliminated through the kidney. Detection and characterization of malignant and benign focal liver lesions with Eovist may help enhance diagnostic accuracy and increase diagnostic confidence.
The American Cancer Society estimates that 21,370 new cases of primary liver cancer and intrahepatic bile duct cancer will be diagnosed in the United States during 2008, and the incidence of liver cancer continues to increase.(1) Earlier staging of primary tumors with metastases in the liver, such as colon cancer, may improve treatment decisions and, hence, the survival rate. This year, approximately 110,000 new cases of colon cancer will be diagnosed in the United States.(2)
Clinical Trials Summary
Eight-hundred sixteen (816) patients with suspected or known focal liver lesions were enrolled in two of four non-randomized, intrapatient-controlled studies that evaluated predominantly the detection (Studies one and two) or morphological characterization (Studies three and four) of liver lesions. Studies one and two ("detection" studies) enrolled patients who were scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and the results from intra-operative ultrasound of the liver. The studies assessed the sensitivity of pre-contrast MRI and Eovist-contrasted MRI for the detection of liver lesions when each set of images was compared to the reference.
Studies three and four ("characterization" studies) enrolled patients with known or suspected focal liver lesions, including patients who were not scheduled for liver surgery. MRI results were compared to a reference standard that consisted of surgical histopathology and other prospectively defined criteria. The studies assessed the correctness of liver lesion characterization by pre-contrast MRI and Eovist-contrasted MRI when each set of images was compared to the reference. Lesions were characterized as one of the following choices: hepatocellular carcinoma, cholangiocarcinoma, metastasis, focal lymphoma, adenoma, focal nodular hyperplasia, hemangioma, abscess, focal liver fibrosis, regenerative nodule, focal fat, hydatid cyst, liver cyst, "not assessable," normal, no lesion or "other."
In all four studies, patients underwent a baseline, pre-contrast MRI followed by the administration of Eovist at a dose of 0.025 mmol/kg body weight, with MRI performed immediately (the "dynamic" phase) and at 10 to 20 minutes following Eovist administration (the "hepatocyte" phase). Patients also underwent computerized tomography with contrast examinations of the liver. Pre-contrast MRI and Eovist-contrasted MR images were evaluated in a systematic, randomized, paired and unpaired fashion by three radiologists who were blinded to clinical information. Computed tomography (CT) images were also evaluated by the radiologists in a separate reading session.
Eovist was generally well-tolerated during the trials. The safety database was based on Eovist exposure in 1,755 adult subjects who received a dose that ranged from 0.003 to 0.5 mmol/kg body weight; the majority (N=1,365) received the recommended dose of 0.025 mmol/kg body weight.
Overall, 4.3% of subjects reported one or more drug-related adverse reactions during a follow-up period that, for most subjects, extended more than 24 hours after Eovist administration. These adverse reactions were predominantly of mild to moderate severity. Serious adverse events were reported among six patients and were attributed to underlying conditions or non-MRI procedures. All serious events occurred more than 10 hours following Eovist administration. The most common adverse reactions at the recommended dose were feeling hot, nausea, headache, injection site reaction (pain, burning, coldness, extravasation), dysgeusia (taste abnormality), flushing, parosmia (smell abnormality), dizziness and vomiting.
About Eovist
Eovist is the first gadolinium-based, liver-specific MRI contrast agent approved in the United States. Eovist enhances the T1-weighted signal. Compared to other extracellular fluid gadolinium-chelate contrast agents, Eovist exhibits a low-level binding to plasma proteins. The resulting higher relaxivity accounts for the lower dose. The recommended dose of Eovist is 0.1 mL/kg body weight (0.025 mmol/kg body weight). Based on its structural properties, Eovist is partially taken up by liver cells, thus enhancing healthy liver tissue (parenchymal enhancement). Lesions with no or minimal hepatocyte function (e.g., cysts, metastases, the majority of hepatocellular carcinomas) will remain unenhanced and will therefore be more readily detected and localized. Eovist provides useful diagnostic information at the time immediately after contrast administration (dynamic imaging) and, thus, also supports lesion characterization (i.e., distinction of malignant and benign types of liver lesions).
Warning: Nephrogenic Systemic Fibrosis
Gadolinium-based contrast agents increase the risk of Nephrogenic Systemic Fibrosis in patients with:
- acute or chronic severe renal insufficiency (glomerular filtration) rate <30 mL/min/1.73 m2), or
- acute renal insufficiency of any severity due to the hepato-renal syndrome or in the perioperative liver transplantation period.
In these patients, avoid the use of gadolinium-based contrast agents unless the diagnostic information is essential and not available with non-contrast enhanced magnetic resonance imaging (MRI). NSF may result in fatal or debilitating systemic fibrosis affecting the skin, muscle and internal organs. Screen all patients for renal dysfunction by obtaining a history and/or laboratory tests. When administering a gadolinium-based contrast agent, do not exceed the recommended dose and allow a sufficient period of time for elimination of the agent from the body prior to any readministration.
As with other contrast media, the possibility of serious or life- threatening anaphylactoid/hypersensitivity reactions with cardiovascular, respiratory and/or cutaneous manifestations should always be considered. The most common adverse reactions observed in clinical trials at the recommended dose included feeling hot, nausea and headache.
Highlights of Eovist Prescribing Information
These highlights do not include all the information needed to use Eovist Injection safely and effectively. See full prescribing information for Eovist Injection.
WARNING: NEPHROGENIC SYSTEMIC FIBROSIS
See full prescribing information for complete boxed warning Gadolinium-based contrast agents increase the risk for nephrogenic systemic fibrosis (NSF) in patients with:
- acute or chronic severe renal insufficiency (glomerular filtration rate <30 mL/min/1.73m2), or
- acute renal insufficiency of any severity due to the hepatorenal syndrome or in the perioperative liver transplantation period.
Indications and Usage
Eovist Injection is a gadolinium-based contrast agent indicated for intravenous use in T1-weighted magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in adults with known or suspected focal liver disease.
Dosage and Administration
The recommended dose of Eovist is 0.1 mL/kg body weight (0.025 mmol/kg body weight) administered undiluted as a single intravenous bolus injection at a flow rate of approximately 2 mL/second. Flush the intravenous cannula with physiological saline solution after the injection.
Dosage Forms and Strengths
Each mL of Eovist Injection contains 181.43 mg gadoxetate disodium (equivalent to 0.25 mol/L gadoxetate disodium) and is available in single use vials.
Contraindications
None
Warnings and Precautions
- Nephrogenic Systemic Fibrosis: see Boxed Warning and Warnings and Precautions.
- Hypersensitivity: anaphylactoid/hypersensitivity reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe reactions including shock can occur. Monitor patients closely for need of emergency cardiorespiratory support.
Adverse Reactions
Adverse reactions reported in clinical studies with a frequency of 0.1% – 1.0% were headache, dizziness, dysgeusia, parosmia, increased blood pressure, flushing, respiratory disorders, vomiting, nausea, rash, pruritus, injection site reactions and feeling hot. (6) To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-842-2937 or FDA at 1-800FDA- 1088 or www.fda.gov/medwatch.
Drug Interactions
Anionic drugs primarily excreted into the bile (such as rifampicin) may reduce the hepatic contrast enhancement and the biliary excretion of Eovist.
Use in Specific Populations
Pregnancy: Based on animal data, may cause fetal harm.
Eovist Patient Counseling Information
Instruct patients receiving Eovist to inform their physician or health care provider of the following:
- if they are pregnant or breast feeding
- if they have a previous history of allergic reaction to contrast media, a history of bronchial asthma or allergic respiratory disorder, or recent administration of a gadolinium based contrast agent
- if they have any history of kidney and/or liver disease
- of all medications they may be taking, including those taken without prescription
Patients with impaired renal function who receive repetitive administrations of a gadolinium-containing contrast agent may have an increased risk for the development of nephrogenic systemic fibrosis if the time interval between the administrations precludes clearance of the contrast agent from the body. In these situations, instruct patients to contact their physician or healthcare provider if they develop burning, itching, swelling, scaling, hardening and tightening of the skin, red or dark patches on the skin, stiffness in joints with trouble moving, bending or straightening the arms, hands, legs or feet, pain deep in the hip bones or ribs, or muscle weakness.
Inform patients that they may experience:
- reactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site
- side effects of feeling hot, nausea, and headache
For additional information on Eovist, please visit www.Imaging.BayerHealthCare.com or call 1-888.84.BAYER.
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Liver Magnetic Resonance Imaging
