Gadoxetate is a paramagnetic contrast agent used during magnetic resonance imaging (MRI) of the liver to detect or assess lesions in patients with known or suspected focal hepatic disease. Approval was based on the results of 4 trials (2 lesion detection trials, 2 lesion morphologic characterization trials). In each trial, patients underwent a baseline pre-contrast MRI followed by a gadoxetate enhanced MRI; images were evaluated by 3 blinded radiologists. For all 3 readers, use of gadoxetate in combination with the pre-contrast images resulted in improved sensitivity for detection and characterizations of hepatic lesions, when compared to pre-contrast images alone. Gadoxetate, like all gadolinium-based contrast agents (GBCAs), carries a black box warning for nephrogenic systemic fibrosis (NSF). NSF is a serious condition that may result in fatal or debilitating fibrosis of the skin, muscle, and internal organs. The propensity to cause NSF differs among available GBCAs; most unconfounded cases have been reported with gadodiamide, gadopentetate dimeglumine, and gadoversetamide. According to the American College of Radiology, an association of gadoxetate with NSF has not been determined. Gadoxetate was FDA-approved in July 2008.
General Administration Information
For storage information, see the specific product information within the How Supplied section.
NOTE: Hypersensitivity reactions may occur. Prior to administration, assess all patients for previous reactions to contrast media. Trained personnel and therapies used to treat hypersensitivity reactions (epinephrine, antihistamines, and corticosteroids) should be readily available. Observe patient for signs and symptoms of hypersensitivity reactions during and after administration.
Route-Specific Administration
Injectable Administration
-Visually inspect for particulate matter and discoloration prior to administration. Solution is clear, colorless to pale yellow. Do not use if discolored or if particulate matter is present.
-Do not mix with other medications. Do not administer other medications in the same IV line.
Intravenous Administration
-Using aseptic technique, draw the solution into a sterile syringe. Administer immediately after obtaining solution from vial. Never pierce the rubber stopper more than once.
-Ensure catheter and venous patency prior to the injection. Extravasation may result in tissue irritation.
-Administer IV at a rate of 1 to 2 mL/second.
-Flush the IV cannula with a normal saline solution after the gadoxetate injection.
-Preform magnetic resonance imaging immediately after the injection. Dynamic imaging consists of the arterial, porto-venous (approximately 60 seconds post-injection), and the blood equilibrium (approximately 120 seconds) phases. Begin hepatocyte imaging approximately 20 minutes (up to 120 minutes) post-injection. However, in patients with elevated concentrations of bilirubin (more than 3 mg/dL) or ferritin, imaging must be performed no later than 60 minutes post-injection.
-Usual safety rules customary for magnetic resonance procedures must be observed.
-Storage: The product contains no antimicrobial preservatives. Discard any unused product.
Cases of nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD) have been reported following administration of gadolinium-based contrast agents (GBCAs) in patients with moderate to severe renal impairment; however, this reaction has not been definitively associated with the use of gadoxetate as a single agent. In fact, an association of any one specific GBCA and the development of NSF/NFD is not always identified; most reports have involved the use of gadodiamide (Omniscan), gadopentetate dimeglumine (Magnevist), and gadoversetamide (OptiMARK). In one retrospective study of 370 patients with severe renal insufficiency, the estimated risk for NSF/NFD was 4%. In a report by the CDC, a case-control study from a single hospital found that the risk of NSF/NFD is higher in patients undergoing peritoneal dialysis compared to hemodialysis (estimated 4.6 cases/100 peritoneal dialysis patients vs. 0.61 cases/100 hemodialysis patients). The mechanism of NSF/NFD in patients receiving GBCAs is unknown; however, dissociation of gadolinium from its chelating agent after intravenous injection is hypothesized. The free gadolinium ion then binds to anions such as phosphate, resulting in an insoluble precipitate that deposits in various tissues, and a fibrotic reaction ensues. NFD is characterized by burning, itching, swelling, scaling, tightening, and hardening of the skin, red or dark patches on the skin, stiffness in joints, resulting in trouble moving, straightening or bending the arms, legs or feet; muscle weakness, pain in hip bones or ribs. NSF involves fibrosis of organs (e.g., heart, liver, lungs) and can lead to death. Diagnosis of NSF/NFD is confirmed by skin biopsy. Patients at risk for NSF due to exposure to GBCAs include certain patients with renal insufficiency and those receiving repeated or higher than recommended doses. Although efficacy of hemodialysis for the prevention of NSF/NFD is unknown, healthcare providers may consider prompt initiation of a hemodialysis session after administration of GBCAs to aid in the elimination of the agent from the body for those patients already receiving hemodialysis. Hemodialysis is preferred to peritoneal dialysis as available data indicate that continuous ambulatory peritoneal dialysis may not be as efficient as hemodialysis in eliminating GBCAs. Treatment options for NSF/NFD are minimal; patients should be enrolled in physical therapy programs. Limited data in support of plasmapheresis or photopheresis are promising.
Cases of acute renal failure (unspecified), some requiring treatment with dialysis, have developed following administration of gadolinium-based contrast agents (GBCAs) to patients with pre-existing chronic renal insufficiencies. However, because gadoxetate is eliminated equally by the renal and hepatobiliary routes, the risk for renal toxicity may be less than with other GBCAs. Acute renal injury appears to be dose-related; therefore, use of the lowest dose necessary for adequate imaging is recommended. Monitor renal function in patients receiving GBCAs.
Anaphylactoid reactions, characterized by cardiovascular, respiratory, and cutaneous symptoms, have been associated with the use of all gadolinium-based contrast agents (GBCAs), including gadoxetate. Most cases develop within 30 minutes of drug administration; however delayed reactions, occurring up to several days after administration, have been reported. Some of the symptoms associated with these reactions may include anaphylactic shock, abdominal pain, conjunctivitis, cough, facial edema, hypoesthesia, hypotension, pallor, pharyngo-laryngeal edema, rhinitis, sneezing, and urticaria. Adverse reactions observed in drug recipients during clinical trials include hypertension (0.4%), flushing (0.3%), rash (unspecified) (0.3%) and maculopapular rash (< 0.1%), pruritus (0.3%), fatigue (0.2%), respiratory distress and dyspnea (0.2%), chills (0.1%), chest pain (unspecified) (0.1%), and feeling abnormal (0.1%). Monitor patients for these symptoms, both during and after drug administration.
Headache (1.1%), dizziness (0.6%), back pain (0.6%), dysgeusia (0.4%), paresthesias (0.3%), parosmia (0.3%), and vertigo (0.1%) were among the most frequently reported adverse events during clinical trials involving gadoxetate. Other neurologic adverse events reported in < 0.1% of drug recipients include akathisia, hyperhidrosis, and tremor. Restlessness was noted during post-marketing use. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
Gastrointestinal adverse events reported by patients receiving gadoxetate during clinical trials include nausea (1.1%), vomiting (0.4%), xerostomia (0.1%), hypersalivation (< 0.1%), and oral discomfort (< 0.1%).
Palpitations and bundle-branch block were observed in less than 0.1% of gadoxetate recipients during clinical trials. Sinus tachycardia has been noted during post-marketing use. Due to the voluntary nature of post-marketing reports, neither a frequency nor a definitive causal relationship can be established.
Injection site reaction (pain, burning, coldness, skin irritation) was reported in 0.4% of gadoxetate recipients during clinical trials. Other adverse events reported by patients and possibly associated with the administration of the drug included malaise (< 0.1%) and feeling hot (0.8%). Take precautions to avoid extravasation and potential tissue irritation, ensure catheter and venous patency prior to administering.
Administration of gadoxetate may result in transient hyperbilirubinemia. During clinical trials, elevated serum bilirubin and iron concentrations were observed in < 1% of drug recipients; however, these abnormal laboratory readings did not exceed 3-times the baseline values, and returned to normal within 1-4 days. According to the manufacturer, determining serum iron concentrations using complexometric methods (i.e., ferrocene complexation method) may result in falsely high or low values for up to 24 hours after gadoxetate administration because of the caloxetate trisodium excipient.
Diagnostic procedures that involve use of contrast agents, such as gadoxetate, should be carried out under direction of a physician with the prerequisite training and a thorough knowledge of the procedure to be performed. As with any paramagnetic contrast agent, use of gadoxetate during contrast enhanced magnetic resonance imaging (MRI) could impair visualization of lesions seen on non-contrast MRI. Caution must be used when contrast-enhanced imaging is interpreted without a companion non-contrast image. Health care providers are also advised of the potential for decreased hepatic contrast in patients with elevated serum ferritin or bilirubin (more than 3 mg/dL) concentrations. If gadoxetate is administered to patients with these laboratory abnormalities, the imaging must be completed within 60 minutes of injection. In addition, gadolinium deposits may remain in patients' bodies for months to years after gadolinium-based contrast agent (GBCA) receipt. Bone has been identified as the main reservoir, retaining the highest concentration of gadolinium (nanomoles per gram of tissue) for the longest duration of time. Other organs which retain lesser amounts of gadolinium include the brain, skin, kidney, liver, and spleen. The consequences of gadolinium retention in the brain have not been established; however, retention in the skin and kidney has been associated with pathologic clinical consequences in patients with impaired renal function. There are rare reports of pathologic skin changes in patients with normal renal function. Other patients who may be at higher risk for gadolinium retention include patients requiring multiple lifetime doses, pregnant women, pediatric patients, and patients with inflammatory conditions. Limit repeated GBCA imaging studies, particularly closely spaced MRI studies, but do not defer or avoid necessary GBCA MRI scans. When choosing a GBCA, consider the retention characteristics of each agent. In general, linear GBCAs result in more retention and retention for longer periods of time than do macrocyclic GBCAs. More specifically, at equivalent doses, use of gadodiamide or gadoversetamide results in higher gadolinium concentrations remaining in the body than gadoxetate disodium, gadopentetate dimeglumine, or gadobenate dimeglumine. Gadolinium concentrations in the body are lowest after administration of gadoterate meglumine, gadobutrol, and gadoteridol. Instruct patients to inform their health care professional about all medical conditions, including if pregnant or thinking about becoming pregnant, dates and numbers of any previous gadolinium-enhanced MRIs, and history of kidney problems.
Ensure the patency and integrity of the intravenous line prior to administering gadoxetate. Take care to avoid extravasation as tissue irritation (inflammation and necrosis) may occur. According to the American College of Radiology (ACR), the risk of significant injury from gadolinium-based contrast agents (GBCA) is extremely low, with GBCAs being much less toxic to the skin/subcutaneous tissue than equal volumes of iodinated contrast media.
Deoxygenated sickle erythrocytes have been shown in vitro to align perpendicular to a magnetic field which may result in vaso-occlusive complications in vivo. The enhancement of magnetic moment by gadolinium-based contrast agents (GBCAs), such as gadoxetate, may possibly potentiate sickle erythrocyte alignment. Although the use of gadoxetate in patients with sickle cell disease and other hemoglobinopathies has not been studied, the American College of Radiology (ACR) manual on contrast media considers any special risk to sickle cell patients from administration of GBCAs to be extremely low; no restrictions for use of GBCAs are recommended by the ACR.
Administration of gadoxetate to patients with a history of severe gadoxetate hypersensitivity is contraindicated. Caution is also recommended for those patients with known gadolinium-based radiopaque contrast media hypersensitivity. The drug has been associated with serious anaphylactic reactions involving cardiovascular, respiratory, and/or cutaneous manifestations. In most cases, these reactions developed within 30 minutes of drug administration. Prior to administration, assess hypersensitivity risk factors in all potential drug recipients. According to the American College of Radiology (ACR), the risk of adverse reactions is approximately 8-times higher in patients with a previous reaction to gadolinium-based contrast media; the subsequent reactions have the potential to be more severe than the first. Other individuals at increased risk include those with a history of asthma, atopy (including hay fever, food allergies, and drug allergies) or other allergic disorders. The manufacturer recommends appropriate facilities (trained personnel and therapies) be available for coping with the emergency treatment of severe reactions, and patients be closely observed for signs and symptoms of a hypersensitivity reaction during and after drug administration. One group of authors recommends taking similar precautions to those that are taken in patients who have previously reacted to iodinated radiopaque contrast media that require subsequent doses. First, the necessity of contrast enhancement during MRI should be determined. If it is determined that contrast enhancement outweighs any potential risk, the intensity of a previous reaction (to either iodinated or gadolinium-based contrast media) should guide precautionary measures. If the previous reaction to contrast media was mild or nonallergic, use of a different or low-osmolar (i.e., gadoteridol or gadodiamide) agent is recommended. If the previous reaction to contrast media was moderate or severe, premedication with steroids (e.g., prednisone or equivalent given 13, 7, and 1 hour prior to the exam; adult dose, 50 mg PO; pediatric dose, 0.5-0.7 mg/kg PO, up to 50 mg) and antihistamines (e.g., diphenhydramine given 1 hour prior to the exam; adult dose 50 mg IV/IM/PO; pediatric dose 1.25 mg/kg PO, up to 50 mg) along with the use of a different or low-osmolar contrast agent is recommended.
Serious adverse reactions, including nephrogenic systemic fibrosis (nephrogenic fibrosing dermopathy) (NSF/NFD), have been reported in patients with renal impairment after receiving gadolinium-based contrast agents (GBCAs), such as gadoxetate. NSF may result in fatal or debilitating systemic fibrosis affecting the internal organs, muscle, and skin. Patients at highest risk for NSF are those with chronic, severe renal disease or renal failure (glomerular filtration rate [GFR] less than 30 mL/minute/1.73 m2) and patients with acute renal injury. Avoid use of GBCAs in patients with impaired drug elimination unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. Use of higher than recommended doses or repeated administration may increase the risk for NSF; therefore, administer the lowest dose necessary for adequate imaging and, if needed, only repeat the dose after a sufficient period of time has passed for elimination of the agent from the body. Gadoxetate is removed by hemodialysis. For patients receiving hemodialysis, it may be prudent to dialyze patients after receiving the contrast agents, although a relationship between dialysis and prevention of NSF has not been determined. Of note, hemodialysis is the preferred method of dialysis as continuous ambulatory peritoneal dialysis does not appear to be as effective in eliminating GBCAs. All patients should be screened for evidence of renal dysfunction by obtaining a medical history or laboratory results prior to the administration of GBCAs. Acute renal injury occurs commonly after surgery, severe infection, injury, or drug-induced renal toxicity. In patients with acute renal injury, serum creatinine concentrations and estimated GFR may not reliably assess renal function; therefore, obtaining a medical history in these patients is of utmost importance. For patients at risk of chronic renal disease (e.g., patients with hypertension, diabetes mellitus, or geriatric patients [older than 60 years of age]), estimate the GFR through laboratory testing. Counsel patients on the signs and symptoms of NSF/NFD. Report possible cases of NSF to the FDA through the FDA Medwatch program at 800-FDA-1088 and to the manufacturer at 888-842-2937. Guidelines confirm kidney function screening is necessary for American College of Radiology (ACR) group III GBCAs, which includes gadoxetate; the risk of NSF with group III GBCAs is likely very low but confirmatory evidence is insufficient, and the lowest diagnostic dose of GBCA should be used. Direct communication between the radiologist and referring provider regarding risk of NSF is suggested for group III GBCA administration in patients with eGFR less than 30 mL/minute/1.73 m2 or acute kidney injury. If multiple urgent group III GBCA doses are indicated, do not delay subsequent dose(s) for NSF concerns. If not urgent, delaying the subsequent dose(s) for more than 24 hours or performing intercurrent dialysis can promote GBCA clearance. In general, do not initiate or alter dialysis based on group III GBCA administration. These recommendations are not altered by patients receiving concomitant nephrotoxic medications, chemotherapy, or contrast-enhanced CT.
Gadoxetate disodium is for intravenous use only. Intrathecal administration of gadolinium-based contrast agents (GBCAs) can cause serious adverse reactions including death, coma, encephalopathy, and seizures. Safety and effectiveness of gadoxetate disodium have not been established with intrathecal use.
Use gadoxetate during pregnancy only if imaging is essential and cannot be delayed. Gadolinium-based contrast agents (GBCAs) cross the placenta and result in fetal exposure and gadolinium retention. Pregnant women may be at greater risk for gadolinium retention. Data on the association between GBCAs and adverse fetal outcomes in human pregnancy are limited and inconclusive. In animal studies, gadoxetate was not found to be teratogenic; however, pre-implantation loss was observed in rats receiving doses at 3.2-times the recommended human dose. In addition, rabbits receiving repeated daily doses of 26-times the recommended human dose experienced post-implantation loss. The American College of Radiology (ACR) manual on contrast media acknowledges that a standard gadolinium-based contrast agent (GBCA) crosses the primate placenta; however, the risk to the human fetus is unknown. Therefore, the ACR advises against GBCA routine use in pregnant women; GBCA should only be administered during pregnancy if absolutely necessary and only after informed consent is obtained. The Guidelines for Computed Tomography and Magnetic Resonance Imaging in Pregnancy and Lactation state that because of the potential for fetal toxicity, the drug should only be used during pregnancy if deemed absolutely essential.
There are no data on the presence of gadoxetate in human milk, the effects on the breast-fed infant, or the effects on milk production. Limited data demonstrates that breast-feeding after administration of another gadolinium-based contrast agent (GBCA) to the mother would result in the infant receiving an oral dose of 0.01% to 0.04% of the maternal dose. Gastrointestinal absorption of a GBCA is limited. In rat lactation studies with radiolabeled gadoxetate, less than 0.5% of the total administered radioactivity was transferred to the nursing pup. The FDA-approved labeling suggests a breast-feeding woman consider interrupting breast-feeding and pumping and discarding breast milk for up to 10 hours after gadoxetate administration to minimize exposure to the breast-fed infant. However, previous American Academy of Pediatrics (AAP) recommendations considered GBCAs compatible with breast-feeding. Additionally, the Guidelines for Computed Tomography and Magnetic Resonance Imaging Use During Pregnancy and Lactation and the American College of Radiology (ACR) manual on contrast media state that lactating women receiving GBCAs can continue to breast-feed without interruption. The reasoning for this recommendation is based on estimates of limited systemic exposure in the breast-fed infant and reviews that conclude maternally administered drug pose no risk to the nursing infant.
For use with magnetic resonance imaging (MRI) to detect and characterize liver lesions in patients with known or suspected focal hepatic disease:
Intravenous dosage:
Adults: 0.1 mL/kg (0.025 mmol/kg) IV as a single dose. Begin dynamic imaging immediately (15 to 25 seconds) after administration. Begin hepatocyte imaging phase approximately 20 minutes (up to 120 minutes) post-injection. For patients with hyperbilirubinemia (more than 3 mg/dL) or elevated ferritin concentrations, imaging must occur no later than 60 minutes post-injection.
Infants, Children, and Adolescents 3 months to 17 years: 0.1 mL/kg (0.025 mmol/kg) IV as a single dose. Begin dynamic imaging immediately (15 to 25 seconds) after administration. Begin hepatocyte imaging phase approximately 20 minutes (up to 120 minutes) post-injection. For patients with hyperbilirubinemia (more than 3 mg/dL) or elevated ferritin concentrations, imaging must occur no later than 60 minutes post-injection.
Maximum Dosage Limits:
-Adults
0.1 mL/kg (0.025 mmol/kg) IV single dose.
-Geriatric
0.1 mL/kg (0.025 mmol/kg) IV single dose.
-Adolescents
0.1 mL/kg (0.025 mmol/kg) IV single dose.
-Children
0.1 mL/kg (0.025 mmol/kg) IV single dose.
-Infants
> 2 months: 0.1 mL/kg (0.025 mmol/kg) IV single dose.
<= 2 months and Premature Infants: Safety and efficacy not established.
-Neonates
Safety and efficacy not established.
Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.
Patients with Renal Impairment Dosing
No dosage adjustments are recommended. Do not exceed the recommended dose and allow sufficient time for elimination prior to any repeat administration. Avoid use in patients with chronic, severe renal disease (GFR < 30 mL/min/1.73m2) and in patients with acute kidney injury unless the diagnostic information is essential and not available with non-contrast imaging or other modalities; these patients are at highest risk for nephrogenic systemic fibrosis.
Intermittent hemodialysis
Gadoxetate is removed from the body by hemodialysis. For patients receiving hemodialysis, consider initiating a hemodialysis session after drug administration in order to enhance clearance of the contrast agent.
*non-FDA-approved indication
There are no drug interactions associated with Gadoxetate Disodium products.
Gadoxetate, a paramagnetic agent, is used to enhance lesion detection and characterization during magnetic resonance imaging (MRI). In magnetic resonance, the visualization of normal or pathological tissue depends on changes in the radiofrequency signal intensity that occur with: differences in proton density; differences of the spin-lattice or longitudinal relaxation time (T1); and differences in the spin-spin or transverse relaxation time (T2). Gadoxetate causes increased signal intensity by developing a magnetic moment when placed in a magnetic field. This magnetic moment enhances the relaxation rates of water protons, thereby shortening T1 and T2 in target tissues. When administered at recommended doses, the effects are primarily observed in the T1 relaxation time.
Gadoxetate is administered intravenously. The plasma concentration time profile of gadoxetate is characterized by a biexponential decline. The total distribution volume of gadoxetate at steady-state is 0.21 L/kg; plasma binding is less than 10%. Gadoxetate does not undergo metabolism. It is eliminated in equal amounts via the renal and hepatobiliary routes. The mean terminal elimination half-life of gadoxetate is approximately 0.9 hours. After administration, gadolinium is present for months or years in brain, bone, skin, and other organs.
Affected cytochrome P450 isoenzymes and drug transporters: none
-Route-Specific Pharmacokinetics
Intravenous Route
The pharmacokinetics of gadoxetate increase proportionally with increasing intravenous doses up to 0.4 mL/kg.
-Special Populations
Hepatic Impairment
Compared to individuals with normal hepatic function, patients with mild to moderate hepatic impairment experience slight to moderate increases in systemic exposure (AUC), half-life, and urinary excretion as well as a decrease in hepatobiliary excretion of gadoxetate; however, the hepatic contrast does not differ between the 2 groups. In patients with severe hepatic impairment (especially in those patients with bilirubin concentrations more than 3 mg/dL), the AUC and half-life of gadoxetate are increased by 60% and 49%, respectively. Hepatobiliary excretion is decreased to approximately 5% in patients with severe hepatic impairment, resulting in a reduced hepatic contrast signal. No difference in safety and imaging performance was observed during clinical trials involving patients with known hepatic cirrhosis (n = 489).
Renal Impairment
In patients with end-stage renal dysfunction, systemic exposure (AUC) and terminal half-life of gadoxetate are increased by 6-fold and 12-fold, respectively. Severe renal impairment may impair imaging performance, especially in those individuals with elevated ferritin concentrations. Moderate increases in AUC and half-life have been observed in patients with moderate renal dysfunction; however, the hepatic contrast in patients with moderate renal dysfunction does not differ from those with normal renal function. A single 3-hour hemodialysis session removes approximately 30% of the drug.
Geriatric
Compared with younger patients, administration of gadoxetate to a geriatric patient results in slight to moderate increases in systemic drug exposure (AUC) and terminal half-life; total body clearance is slightly decreased in geriatric patients. No clinically relevant differences in enhanced hepatic contrast have been observed between the 2 groups.