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Black Box Warning
WARNING:
See full prescribing information for complete Boxed Warning.
NEPHROGENIC SYSTEMIC FIBROSIS (NSF):
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 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 (for example, 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 EOVIST dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration
Overview
Gadoxetate is a Diagnostic Agent that is FDA approved for the diagnosis of known or suspected focal liver disease through MRI. There is a Black Box Warning for this drug as shown here. Common adverse reactions include nausea, headache, feeling hot, dizziness, and back pain.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
Indications
EOVIST is indicated for intravenous use in magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in patients with known or suspected focal liver disease.
Dosage
Recommended Dose
The recommended dose of EOVIST is 0.1 mL/kg body weight (0.025 mmol/kg body weight).
2.2 Drug Handling and Administration
Use sterile technique when preparing and administering EOVIST
Visually inspect EOVIST, supplied in a single-use vial, for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is present
Use EOVIST immediately after obtaining appropriate dose from vial. The rubber stopper should never be pierced more than once. Discard any unused portion of an EOVIST vial
Administer EOVIST undiluted as an intravenous bolus injection at a flow rate of approximately 2 mL/second
Do not mix EOVIST with other medications and do not administer EOVIST in the same intravenous line simultaneously with other medications
Flush the intravenous cannula with a normal saline solution after EOVIST injection
Imaging can commence immediately following EOVIST administration
2.3 Imaging
Liver lesions are detected and characterized with pre-contrast MRI and EOVIST MRI obtained during dynamic and hepatocyte imaging phases. Perform a pre-contrast MRI, inject EOVIST and begin dynamic imaging approximately 15–25 seconds after completion of the injection. Dynamic imaging consists of the arterial, the porto-venous (approximately 60 seconds post-injection), and the blood equilibrium (approximately 120 seconds) phases.
Begin the hepatocyte imaging phase approximately 20 minutes post-injection. Hepatocyte phase imaging may be performed up to 120 minutes post-injection.
Elevated intrinsic levels of bilirubin (>3 mg/dL) or ferritin can reduce the hepatic contrast effect of EOVIST. Perform MR imaging no later than 60 minutes following EOVIST administration to patients with these laboratory abnormalities, including patients who have elevated ferritin levels due to hemodialysis [see Warnings and Precautions (5.6) and Use in Specific Populations (8.6, 8.7)].
Lesions with no or minimal hepatocyte function (cysts, metastases, and the majority of hepatocellular carcinomas) generally will not accumulate EOVIST. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a diagnosis of hepatocellular carcinoma.
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Gadoxetate in adult patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoxetate in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
Safety and effectiveness in pediatric patients has not been established.
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information regarding Off-Label Guideline-Supported Use of Gadoxetate in pediatric patients.
Non–Guideline-Supported Use
There is limited information regarding Off-Label Non–Guideline-Supported Use of Gadoxetate in pediatric patients.
Contraindications
EOVIST is contraindicated in patients with history of severe hypersensitivity reactions to EOVIST.
Warnings
WARNING:
See full prescribing information for complete Boxed Warning.
NEPHROGENIC SYSTEMIC FIBROSIS (NSF):
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 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 (for example, 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 EOVIST dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration
Nephrogenic Systemic Fibrosis (NSF)
Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following EOVIST administration to Bayer HealthCare (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch).
Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.
Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to a patient. For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow a sufficient period of time for elimination of the drug prior to any re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. The usefulness of hemodialysis in the prevention of NSF is unknown.
5.2 Hypersensitivity Reactions
Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe, including shock have uncommonly occurred following EOVIST administration [see Adverse Reactions (6)].
Before EOVIST administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to EOVIST.
Administer EOVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.
Most hypersensitivity reactions to EOVIST have occurred within half an hour after administration. Delayed reactions can occur up to several days after EOVIST administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following EOVIST administration.
5.3 Acute Kidney Injury
In patients with chronic renal impairment, acute kidney injury sometimes requiring dialysis has been observed with the use of some GBCAs. The risk of acute kidney injury might be lower with EOVIST due to its dual excretory pathways. Do not exceed the recommended dose; the risk of acute kidney injury may increase with higher than recommended doses.
5.4 Extravasation and Injection Site Reactions
Ensure catheter and venous patency before the injection of EOVIST. Extravasation into tissues during EOVIST administration may result in local tissue reactions. Strictly avoid intramuscular administration of EOVIST because it may cause myocyte necrosis and inflammation [see Nonclinical Toxicology (13.2)].
5.5 Interference with Laboratory Tests
Serum iron determination using complexometric methods (for example, ferrocene complexation method) may result in falsely high or low values for up to 24 hours after the examination with EOVIST because of the caloxetate trisodium excipients [see Adverse Reactions (6.1)].
5.6 Interference with Visualization of Liver Lesions
Severe renal or hepatic failure may impair EOVIST imaging performance. In patients with end-stage renal failure, hepatic contrast was markedly reduced and was attributed to elevated serum ferritin levels. In patients with abnormally high (>3 mg/dL) serum bilirubin, reduced hepatic contrast was observed. If EOVIST is used in these patients, complete MRI no later than 60 minutes after EOVIST administration and use a paired non-contrast and contrast MRI set for diagnosis.
Adverse Reactions
Clinical Trials Experience
The following serious adverse reactionsare discussed elsewhere in the labeling:
Nephrogenic systemic fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.1)]
Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)]
6.1 Clinical Trials Experience
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
The adverse reactions described in this section reflect EOVIST exposure in 1,989 subjects with the majority (1,581 subjects) receiving the recommended dose. Overall, 59% of the subjects were men and the ethnic distribution was 64% Caucasian, 22% Asian, 3% Hispanic, 2% Black, and 0.5% of subjects consisted of other ethnic groups. The average age was 57 years (age range from 19 to 84 years).
Overall, 4% of subjects reported one or more adverse reactions following EOVIST administration. The most frequent (≥ 0.5%) adverse reactions associated with the use of EOVIST were nausea, headache, feeling hot, dizziness, and back pain. Adverse reactions were predominantly of mild to moderate severity.
Table 1 lists adverse reactions that occurred in ≥ 0.1% of subjects treated with EOVIST.
Adverse reactions that occurred with a frequency of < 0.1% in subjects who received EOVIST include: tremor, akathisia, bundle branch block, palpitation, oral discomfort, salivary hypersecretion, maculopapular rash, hyperhidrosis, discomfort, and malaise.
Elevation of serum iron values and serum bilirubin laboratory values were reported in less than 1% of patients after administration of EOVIST. The values did not exceed more than 3 times the baseline values and returned to baseline within 1 to 4 days.
Postmarketing Experience
The following additional adverse reactions have been reported during the postmarketing use of EOVIST. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Hypersensitivity reactions (anaphylacticshock, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough and pallor) [see Warnings and Precautions (5.2)]
Tachycardia
Restlessness
Drug Interactions
There is limited information regarding Gadoxetate Drug Interactions in the drug label.
There are no studies of EOVIST in pregnant women to inform the drug-associated risk. Gadolinium-based contrast agents (GBCAs) are reported to cross the placenta and limited published data do not report adverse effects in neonates who were exposed to GBCAs in-utero. The background risk of major birth defects and miscarriage for the indicated population is unknown. However, the background risk in the U.S. general population of major birth defects is 2 to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies. No teratogenicity was observed with repeated daily intravenous administration of gadoxetate disodium to rats during organogenesis at doses up to 32 times the recommended single human dose; however, an increase in preimplantation loss was noted at doses 3.2 times the single human dose. Post implantation loss was observed with repeated daily intravenous administration of gadoxetate disodium to rabbits on gestation days 6 through 18 at doses 26 times the recommended single human dose [see Data]. Advise pregnant women of the potential risk to a fetus.
Data
Animal Data
Animal reproductive and developmental toxicity studies were done in rats and rabbits. Gadoxetate disodium was not teratogenic when given intravenously during organogenesis to pregnant rats at doses up to 32 times the recommended single human dose (mmol/m2 basis). However, an increase in preimplantation loss was noted at 3.2 times the human dose (mmol/m2 basis). Compared to untreated controls, rates of postimplantation loss and absorption increased and litter size decreased when pregnant rabbits received gadoxetate disodium at doses 26 times the recommended human single dose (mmol/m2 basis). This occurred without evidence of maternal toxicity. Because pregnant animals received repeated daily doses of gadoxetate disodium, their overall exposure was significantly higher than that achieved with the standard single dose administered to humans.
Pregnancy Category (AUS):
Australian Drug Evaluation Committee (ADEC) Pregnancy Category
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Gadoxetate in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Gadoxetate during labor and delivery.
Nursing Mothers
Risk Summary
There is no information regarding the presence of gadoxetate disodium in human milk, the effects of the drug in a breastfed infant, or the effects of the drug on milk production. However, published lactation data on other GBCAs report that 0.01 to 0.04% of the maternal gadolinium dose is present in breast milk and there is limited GBCA gastrointestinal absorption in the breastfed infant. In rat lactation studies with [153Gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the nursing pup.
Clinical Considerations
A lactating woman may consider interrupting breastfeeding and pumping and discarding breast milk for up to 10 hours after EOVIST administration in order to minimize exposure to a breastfed infant.
Data
Animal Data
In lactating rats given 0.1 mmol/kg [153Gd] gadoxetate disodium, less than 0.5% of the total administered radioactivity was transferred to the neonates via maternal milk, mostly within 2 hours.
Pediatric Use
Adequate and well-controlled studies of EOVIST in pediatric patients have not been conducted. An observational study with EOVIST was performed in 52 patients (aged > 2 months and < 18 years) referred for evaluation of suspected or known focal liver lesions. EOVIST improved border delineation and increased contrast of the primary lesion in the majority of patients when compared to non-contrast images. No safety issues were identified.
No dose adjustment according to age is necessary in pediatric patients. The safety and effectiveness of EOVIST have not been established in premature infants.
NSF Risk
No case of NSF associated with EOVIST or any other GBCA has been identified in pediatric patients ages 6 years and younger.
Juvenile Animal Data
Single and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of a specific risk for use in pediatric patients including term neonates and infants.
Geriatic Use
In clinical studies of EOVIST, 674 (34%) patients were 65 years of age and over, while 20 (1%) were 80 years of age and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, use of EOVIST in an elderly patient should be cautious, reflecting the greater frequency of decreased hepatic, renal or cardiac function and of concomitant disease or other drug therapy.
In a clinical pharmacology study, slight to moderate differences in pharmacokinetic parameters of gadoxetate disodium (increased AUC and terminal half-life, decreased total clearance) were found in a group of geriatric volunteers in comparison to non-geriatric volunteers. No clinically relevant differences in liver contrast enhancement were found.
Gender
There is no FDA guidance on the use of Gadoxetate with respect to specific gender populations.
Race
There is no FDA guidance on the use of Gadoxetate with respect to specific racial populations.
Renal Impairment
In a clinical pharmacology study in a group of patients with moderate renal impairment, a moderate increase in AUC and terminal half-life was observed in comparison to healthy volunteers with normal renal function. Hepatic contrast did not differ among the groups.
End-stage renal failure may impair EOVIST imaging performance [see Warnings and Precautions (5.6)]. In a study of patients with end-stage renal failure, the terminal half-life was prolonged about 12-fold and the AUC was increased about 6-fold. Hepatic contrast was markedly reduced in these patients, which was attributed to significantly elevated serum ferritin levels [see Warnings and Precautions (5.1)].Approximately 30% of the injected dose was removed by dialysis in a single 3-hour dialysis session, which started one hour after an EOVIST dose. EOVIST was almost completely eliminated via dialysis and biliary excretion within the observation period of 6 days, predominantly within the first 3 days.
Hepatic Impairment
In a clinical pharmacology study in groups of patients with mild or moderate hepatic impairment, a slight to moderate increase in plasma AUC, half-life and urinary excretion, as well as decrease in hepatobiliary excretion was observed in comparison to healthy subjects with normal liver function. Hepatic contrast signal did not differ among the groups.
Severe hepatic impairment may impair EOVIST imaging performance [see Warnings and Precautions (5.6)].In patients with severe hepatic impairment, especially in patients with abnormally high (> 3 mg/dL) serum bilirubin levels, the AUC was increased up to 60% and the elimination half-life was increased up to 49%. The hepatobiliary excretion substantially decreased to about 5% of the administered dose and reduced hepatic contrast signal was observed.
A dose adjustment is not necessary for patients with hepatic impairment.
In clinical studies, 489 patients had a diagnosis of liver cirrhosis (Child-Pugh category A, n = 270; category B, n = 98; category C, n = 24; unknown category, n = 97). No difference in diagnostic performance and safety was observed among these patients.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Gadoxetate in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Gadoxetate in patients who are immunocompromised.
Administration and Monitoring
Administration
Intravenous
Monitoring
There is limited information regarding Monitoring of Gadoxetate in the drug label.
IV Compatibility
There is limited information regarding IV Compatibility of Gadoxetate in the drug label.
Overdosage
The maximum dose studied in MR imaging was 0.4 mL/kg (0.1 mmol/kg) body weight and was tolerated in a manner similar to lower doses. In case of inadvertent overdosage in patients with severely impaired renal and/or hepatic function, EOVIST can be partially removed by hemodialysis
Pharmacology
There is limited information regarding Gadoxetate Pharmacology in the drug label.
