DESCRIPTION SECTION.

11DESCRIPTION. EOVIST (gadoxetate disodium) is paramagnetic contrast agent administered for MRI. EOVIST is provided as sterile, clear, colorless to pale yellow aqueous solution for intravenous injection.EOVIST contains the active pharmaceutical ingredient, gadoxetate disodium (Gd-EOB-DTPA). The chemical name for gadoxetate disodium is (4S)-4-(4-Ethoxybenzyl)-3,6,9-tris(carboxylatomethyl)-3,6,9-triazaundecanedioic acid, gadolinium complex, disodium salt. Gadoxetate disodium has molecular weight of 725.72 and an empirical formula of GdC23H28N3O11Na2. The structural formula of gadoxetate disodium in aqueous solution is:Each mL of EOVIST contains 181.43 mg (0.25 mmol) of gadoxetate disodium with 1.00 mg of caloxetate trisodium, 1.21 mg of trometamol, hydrochloric acid and/or sodium hydroxide (for pH adjustment), and water for injection. EOVIST contains no antimicrobial preservative.Pertinent physiochemical properties of EOVIST are provided in Table 2.Table Physicochemical PropertiesOsmolality at 37C (Osm/kg H2O)0.688Viscosity at 37C (cP)1.19 Density at 37C (g/mL)1.088pH6.8-8. Density at 37C (g/mL). Structure.

ADVERSE REACTIONS SECTION.

6ADVERSE REACTIONS. The following serious adverse reactions are discussed elsewhere in the labeling:oNephrogenic systemic fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.1)]oHypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)]. oNephrogenic systemic fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.1)]. oHypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)]. Most common adverse reactions (incidence >= 0.5%) are nausea, headache, feeling hot, dizziness, and back pain (6)To report SUSPECTED ADVERSE REACTIONS, contact Bayer HealthCare Pharmaceuticals Inc. at 1-888-84-BAYER (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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 lists adverse reactions that occurred in >= 0.1% of subjects treated with EOVIST.Table Adverse ReactionsReactionRate (%)n 1581Nausea1.1Headache1.1Feeling hot0.8Dizziness0.6Back pain0.6Vomiting0.4Blood pressure increased 0.4Injection site reactions (pain, burning, coldness, extravasation, irritation)0.4Dysgeusia0.4Paresthesia0.3Flushing0.3Parosmia0.3Pruritus (generalized, eye)0.3Rash0.3Respiratory disorders (dyspnea, respiratory distress)0.2Fatigue0.2Chest pain0.1Vertigo0.1Dry mouth0.1Chills0.1Feeling abnormal0.1Adverse reactions that occurred with 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 times the baseline values and returned to baseline within to days.. 6.2Postmarketing Experience. The following additional adverse reactions have been reported during the postmarketing use of EOVIST. Because these reactions are reported voluntarily from population of uncertain size, it is not possible to reliably estimate their frequency or establish causal relationship to drug exposure.oHypersensitivity reactions (anaphylactic shock, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough and pallor) [see Warnings and Precautions (5.2)]oTachycardiaoRestlessness oGeneral Disorders and Administration Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.oSkin: Gadolinium associated plaques. oHypersensitivity reactions (anaphylactic shock, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough and pallor) [see Warnings and Precautions (5.2)]. oTachycardia. oRestlessness oGeneral Disorders and Administration Site Conditions: Adverse events with variable onset and duration have been reported after GBCA administration [see Warnings and Precautions (5.3)]. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems.. oSkin: Gadolinium associated plaques.

ANIMAL PHARMACOLOGY & OR TOXICOLOGY SECTION.

13.2 Animal Toxicology and/or Pharmacology. dose-related increase in QTc which was resolved by 30 minutes post dosing was observed in dogs when given single dose of EOVIST. The increase was noted when given in doses equal to or greater than 0.1 mmol/kg (2.2 times the human dose). Maximum increase in QTcF was equal to or less than 20 ms at doses up to 0.5 mmol/kg (11 times the human dose).A gait disturbance was observed in of mice when given EOVIST at dose of approximately 1.1 mmol/kg (3.6 times the human dose); the disturbance occurred at 30 minutes post dosing and resolved at hours post dosing.Local intolerance reactions, including moderate interstitial hemorrhage, edema, and focal muscle fiber necrosis, were observed after intramuscular administration of EOVIST [see Warning and Precautions 5.5 )].

BOXED WARNING SECTION.

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.oThe risk for NSF appears highest among patients with:oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), oroAcute kidney injury.oScreen 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 sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)]. oThe risk for NSF appears highest among patients with:oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), oroAcute kidney injury.. oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), or. oAcute kidney injury.. oScreen 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. WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF) See full prescribing information for complete boxed warning.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.oThe risk for NSF appears highest among patients with:oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), oroAcute kidney injury.oScreen 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 (5.1).. oThe risk for NSF appears highest among patients with:oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), oroAcute kidney injury.. oChronic, severe kidney disease (GFR 30 mL/min/1.73m2), or. oAcute kidney injury.. oScreen patients for acute kidney injury and other conditions that may reduce renal function.

CARCINOGENESIS & MUTAGENESIS & IMPAIRMENT OF FERTILITY SECTION.

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity studies of EOVIST have been conducted.Gadoxetate disodium was not mutagenic in in vitro reverse mutation tests in bacteria, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of doses up to mmol/kg.Gadoxetate disodium had no effect on fertility and general reproductive performance of male and female rats when given in doses 6.5 times the human dose (based on body surface area).

CLINICAL PHARMACOLOGY SECTION.

12CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Gadoxetate disodium is paramagnetic compound and develops magnetic moment when placed in magnetic field. The relatively large magnetic moment produced by gadoxetate disodium results in local magnetic field, yielding enhanced relaxation rates (shortening of relaxation times) of water protons in the vicinity of the paramagnetic agent, which leads to an increase in signal intensity (brightening) of blood and tissue.In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in magnetic field, gadoxetate disodium decreases the T1 and T2 relaxation time in target tissue. At the recommended dose, the effect is observed with greatest sensitivity in T1-weighted MR sequences.. 12.2Pharmacodynamics. EOB-DTPA forms stable complex with the paramagnetic gadolinium ion with thermodynamic stability of log KGdL=-23.46. Gadoxetate disodium is highly water-soluble, hydrophilic compound with lipophilic moiety, the ethoxybenzyl group (EOB). Gadoxetate disodium shows weak (<10%), transient protein binding and the relaxivity in plasma is about 8.7 L/mmol/sec at pH 7, 39C and 0.47 T.Gadoxetate disodium is selectively taken up by hepatocytes [see Clinical Pharmacology (12.3)] resulting in increased signal intensity in liver tissue [see Dosage and Administration (2.3)].EOVIST exhibits biphasic mode of action: first, distribution in the extracellular space after injection and subsequently, selective uptake by hepatocytes (and biliary excretion) due to the lipophilic (EOB) moiety.. 12.3Pharmacokinetics. DistributionAfter intravenous administration, the plasma concentration time profile of gadoxetate disodium is characterized by bi-exponential decline. The total distribution volume of gadoxetate disodium at steady state is about 0.21 L/kg (extracellular space); plasma protein binding is less than 10%. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)]. EliminationGadoxetate disodium is equally eliminated via the renal and hepatobiliary routes. The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22-39 years of age to be 0.91 to 0.95 hour. Clearance appeared to decrease slightly with increasing age. The pharmacokinetics are dose-linear up to dose of 0.4 mL/kg (0.1 mmol/kg), which is times the recommended dose [see Use in Specific Populations (8.4, 8.5, 8.6, and8.7)]. total serum clearance (Cltot) was 250 mL/min, whereas the renal clearance (Clr) corresponds to about 120 mL/min, value similar to the glomerular filtration rate in healthy subjects.MetabolismGadoxetate disodium is not metabolized.

CLINICAL STUDIES SECTION.

14CLINICAL STUDIES. 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 and 2) or morphological characterization (studies and 4) of liver lesions. Studies and (detection studies) enrolled patients who were scheduled for liver surgery. MRI results were compared to 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 and (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 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 baseline, pre-contrast MRI followed by the administration of EOVIST at dose of 0.025 mmol/kg, 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 systematic, randomized, paired and unpaired fashion by three radiologists who were blinded to clinical information. CT images were also evaluated by the radiologists in separate reading session.Diagnostic efficacy was determined in 621 patients. The average age was 57 years (range 19 to 84 years) and 54% were male. The ethnic representations were 90% Caucasian, 4% Black, 3% Hispanic, 2% Asian, and 1% of other ethnic groups.The combination of non-contrasted and EOVIST-contrasted MR images had improved sensitivity for the detection and characterization of liver lesions, compared to pre-contrasted MR images (Tables and 4). The improved sensitivity in detection of lesions was predominantly related to the detection of additional lesions among patients with multiple lesions on the pre-contrast MR images. The false positive rates for detection of lesions were similar for non-contrasted MR images and EOVIST-contrasted MR images (32% versus 34%, respectively). Liver lesion detection and characterization results were similar between CT and the combination of pre-contrasted and EOVIST-contrasted MR images.Table Sensitivity in Liver Lesion DetectionDiagnostic ProcedureReaderStudy 1Sensitivity (%)n=129Study 2Sensitivity (%)n=126Pre-contrast MRIReader 17677Reader 27673Reader 37172Combined pre- and EOVIST-contrast MRIReader 18182Reader 27876Reader 37478Difference:combined pre EOVIST-contrast MRI minus pre MRI(95% confidence interval)Reader 15 (1, 9)5 (1, 9)Reader 22 (-1, 5)3 (-1, 7)Reader 33 (0, 6)6 (0, 10) Statistically significant improvementTable Proportion of Correctly Characterized LesionsStudy 3Study 4Diagnostic ProcedureReadernProportion correct (%) nProportion correct (%) Pre-contrast MRIReader 11825117760Reader 21825917764Reader 31825317748Combined pre- and EOVIST-contrast MRIReader 11826717761Reader 21827617776Reader 31825817767Difference: combined pre- and EOVIST-contrast MRI minuspre-contrast MRI(95% confidence interval)Reader 116 (7, 25)1 (-7, 10)Reader 217 (9, 25)11 (5, 18)Reader 35 (-2, 12)19 (11, 27) Statistically significant improvement Proportion of correctly characterized lesions with respect to the reference.

CONTRAINDICATIONS SECTION.

4CONTRAINDICATIONS. EOVIST is contraindicated in patients with history of severe hypersensitivity reactions to EOVIST [see Warnings and Precautions (5.2)].. History of severe hypersensitivity reaction to EOVIST (4).

MECHANISM OF ACTION SECTION.

12.1Mechanism of Action. Gadoxetate disodium is paramagnetic compound and develops magnetic moment when placed in magnetic field. The relatively large magnetic moment produced by gadoxetate disodium results in local magnetic field, yielding enhanced relaxation rates (shortening of relaxation times) of water protons in the vicinity of the paramagnetic agent, which leads to an increase in signal intensity (brightening) of blood and tissue.In MRI, visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with 1) differences in proton density; 2) differences of the spin-lattice or longitudinal relaxation times (T1); and 3) differences in the spin-spin or transverse relaxation time (T2). When placed in magnetic field, gadoxetate disodium decreases the T1 and T2 relaxation time in target tissue. At the recommended dose, the effect is observed with greatest sensitivity in T1-weighted MR sequences.

DOSAGE & ADMINISTRATION SECTION.

2.2Drug Handling and Administration. oUse sterile technique when preparing and administering EOVISToVisually inspect EOVIST, supplied in single-dose container (vial), for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is presentoUse 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 vialoAdminister EOVIST undiluted as an intravenous injection at recommended rate of mL to mL per second.oDo not mix EOVIST with other medications and do not administer EOVIST in the same intravenous line simultaneously with other medicationsoFlush the intravenous cannula with normal saline solution after EOVIST injectionoImaging can commence immediately following EOVIST administration. oUse sterile technique when preparing and administering EOVIST. oVisually inspect EOVIST, supplied in single-dose container (vial), for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is present. oUse 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. oAdminister EOVIST undiluted as an intravenous injection at recommended rate of mL to mL per second.. oDo not mix EOVIST with other medications and do not administer EOVIST in the same intravenous line simultaneously with other medications. oFlush the intravenous cannula with normal saline solution after EOVIST injection. oImaging can commence immediately following EOVIST administration. 2.3Imaging. oLiver lesions are detected and characterized with pre-contrast MRI and EOVIST MRI obtained during dynamic and hepatocyte imaging phases. Perform 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. oBegin the hepatocyte imaging phase approximately 20 minutes post-injection. Hepatocyte phase imaging may be performed up to 120 minutes post-injection.oElevated 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)].oLesions 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 diagnosis of hepatocellular carcinoma. oLiver lesions are detected and characterized with pre-contrast MRI and EOVIST MRI obtained during dynamic and hepatocyte imaging phases. Perform 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. oBegin the hepatocyte imaging phase approximately 20 minutes post-injection. Hepatocyte phase imaging may be performed up to 120 minutes post-injection.. oElevated 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)].. oLesions 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 diagnosis of hepatocellular carcinoma.

DOSAGE FORMS & STRENGTHS SECTION.

3DOSAGE FORMS AND STRENGTHS. EOVIST is sterile, clear, and colorless to pale yellow solution for injection containing 181.43 mg gadoxetate disodium per mL (equivalent to 0.25 mmol gadoxetate disodium per mL) supplied in single-dose containers (vials).. Injection: 181.43 mg/mL in single-dose containers (vials) (3).

GERIATRIC USE SECTION.

8.5Geriatric 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 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 group of geriatric volunteers in comparison to non-geriatric volunteers. No clinically relevant differences in liver contrast enhancement were found.

HOW SUPPLIED SECTION.

16HOW SUPPLIED/STORAGE AND HANDLING. 16.1How Supplied. EOVIST is supplied in single-dose, rubber stoppered containers (vials) containing 181.43 mg/mL of gadoxetate disodium (equivalent to 0.25 mmol/mL gadoxetate disodium), in the following sizes: 10 mL single-dose containers (vials) filled with 10 mL, boxes of 5(NDC 50419-320-05). 10 mL single-dose containers (vials) filled with 10 mL, boxes of 5(NDC 50419-320-05). 16.2Storage and Handling. Store at temperatures between 20 to 25 (68 to 77 F); excursions permitted to 15 to 30 (59 to 86) [see USP Controlled Room Temperature].EOVIST is ready-to-use solution for single use only. Visually inspect EOVIST for particulate matter and discoloration prior to administration. Do not use the solution if it is discolored or if particulate matter is present. The rubber stopper should not be pierced more than once. Use EOVIST immediately after opening. Unused portions should be discarded.

INDICATIONS & USAGE SECTION.

1INDICATIONS AND USAGE. 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.. EOVIST is gadolinium-based contrast agent indicated for use in magnetic resonance imaging (MRI) of the liver to detect and characterize lesions in patients with known or suspected focal liver disease (1).

INFORMATION FOR PATIENTS SECTION.

17PATIENT COUNSELING INFORMATION. oAdvise the patient to read the FDA-approved patient labeling (Medication Guide).Nephrogenic Systemic Fibrosis Instruct patients to inform their physician if they:oHave history of kidney disease and/or liver diseaseoHave recently received GBCAGBCAs increase the risk of NSF among patients with impaired elimination of drugs. To counsel patients at risk of NSF:oDescribe the clinical manifestations of NSFoDescribe procedures to screen for the detection of renal impairmentInstruct the patients to contact their physician if they develop signs or symptoms of NSF following EOVIST administration, such as 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 in the hip bones or ribs; or muscle weakness.Common Adverse Reactions Inform patients that they may experience: oReactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site oSide effects of headache, nausea, abnormal taste and feeling hotGeneral Precautions Gadolinium RetentionoAdvise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.3)].Instruct patients receiving EOVIST to inform their physician if they:oAre pregnant or breastfeedingoHave history of allergic reaction to contrast media, bronchial asthma or allergic respiratory disorder(C) 2008, Bayer HealthCare Pharmaceuticals Inc., All rights reserved.Manufactured for:Bayer HealthCare Pharmaceuticals Inc.Whippany, NJ 07981 Manufactured in Germany. oAdvise the patient to read the FDA-approved patient labeling (Medication Guide).. oHave history of kidney disease and/or liver disease. oHave recently received GBCA. oDescribe the clinical manifestations of NSF. oDescribe procedures to screen for the detection of renal impairment. oReactions along the venous injection site, such as mild and transient burning or pain or feeling of warmth or coldness at the injection site oSide effects of headache, nausea, abnormal taste and feeling hot. oAdvise patients that gadolinium is retained for months or years in brain, bone, skin, and other organs in patients with normal renal function. The clinical consequences of retention are unknown. Retention depends on multiple factors and is greater following administration of linear GBCAs than following administration of macrocyclic GBCAs [see Warnings and Precautions (5.3)].. oAre pregnant or breastfeeding. oHave history of allergic reaction to contrast media, bronchial asthma or allergic respiratory disorder.

LACTATION SECTION.

8.2 Lactation Risk SummaryThere is no information regarding the presence of gadoxetate disodium in human milk, the effects of the drug in 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 ConsiderationsA 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 breastfed infant.DataAnimal DataIn 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 hours.

NONCLINICAL TOXICOLOGY SECTION.

13NONCLINICAL TOXICOLOGY. 13.1Carcinogenesis, Mutagenesis, Impairment of Fertility. No carcinogenicity studies of EOVIST have been conducted.Gadoxetate disodium was not mutagenic in in vitro reverse mutation tests in bacteria, or in chromosome aberration tests in human peripheral blood lymphocytes, and was negative in an in vivo micronucleus test in mice after intravenous injection of doses up to mmol/kg.Gadoxetate disodium had no effect on fertility and general reproductive performance of male and female rats when given in doses 6.5 times the human dose (based on body surface area).. 13.2 Animal Toxicology and/or Pharmacology. dose-related increase in QTc which was resolved by 30 minutes post dosing was observed in dogs when given single dose of EOVIST. The increase was noted when given in doses equal to or greater than 0.1 mmol/kg (2.2 times the human dose). Maximum increase in QTcF was equal to or less than 20 ms at doses up to 0.5 mmol/kg (11 times the human dose).A gait disturbance was observed in of mice when given EOVIST at dose of approximately 1.1 mmol/kg (3.6 times the human dose); the disturbance occurred at 30 minutes post dosing and resolved at hours post dosing.Local intolerance reactions, including moderate interstitial hemorrhage, edema, and focal muscle fiber necrosis, were observed after intramuscular administration of EOVIST [see Warning and Precautions 5.5 )].

OVERDOSAGE SECTION.

10OVERDOSAGE. The maximum dose studied in MR imaging was 0.4 mL/kg (0.1 mmol/kg) body weight and was tolerated in 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 [see Use in Specific Populations (8.6)].

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL.

Carton x 10 mL NDC 50419-320-055 vials of 10 mLsterile solutionEovist(R) 10 mL(gadoxetate disodium)Injection0.25 mol/LRx onlyEach mL contains 181.43 gadoxetate disodium and the excipients caloxetate trisodium, trometamol, hydrochloric acid and/or sodium hydroxide (for pH adjustment), and water for injection. Eovist(R) contains no antimicrobial preservative.Single-dose container.Discard unused portion.Store at 20-25C (68-77F); excursions permitted to 15-30C [See USP Controlled Room Temperature.] For intravenous administration.Dosage: See package insert.Mfd. for:Bayer HealthCare Pharmaceuticals Inc.Wayne, NJ 07470Mfd. in Germany Eovist 10 mL carton.

PEDIATRIC USE SECTION.

8.4Pediatric 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 RiskNo case of NSF associated with EOVIST or any other GBCA has been identified in pediatric patients ages years and younger.Juvenile Animal DataSingle and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of specific risk for use in pediatric patients including term neonates and infants.

PHARMACODYNAMICS SECTION.

12.2Pharmacodynamics. EOB-DTPA forms stable complex with the paramagnetic gadolinium ion with thermodynamic stability of log KGdL=-23.46. Gadoxetate disodium is highly water-soluble, hydrophilic compound with lipophilic moiety, the ethoxybenzyl group (EOB). Gadoxetate disodium shows weak (<10%), transient protein binding and the relaxivity in plasma is about 8.7 L/mmol/sec at pH 7, 39C and 0.47 T.Gadoxetate disodium is selectively taken up by hepatocytes [see Clinical Pharmacology (12.3)] resulting in increased signal intensity in liver tissue [see Dosage and Administration (2.3)].EOVIST exhibits biphasic mode of action: first, distribution in the extracellular space after injection and subsequently, selective uptake by hepatocytes (and biliary excretion) due to the lipophilic (EOB) moiety.

PHARMACOKINETICS SECTION.

12.3Pharmacokinetics. DistributionAfter intravenous administration, the plasma concentration time profile of gadoxetate disodium is characterized by bi-exponential decline. The total distribution volume of gadoxetate disodium at steady state is about 0.21 L/kg (extracellular space); plasma protein binding is less than 10%. Following GBCA administration, gadolinium is present for months or years in brain, bone, skin, and other organs [see Warnings and Precautions (5.3)]. EliminationGadoxetate disodium is equally eliminated via the renal and hepatobiliary routes. The mean terminal elimination half-life of gadoxetate disodium (0.01 to 0.1 mmol/kg) has been observed in healthy volunteers of 22-39 years of age to be 0.91 to 0.95 hour. Clearance appeared to decrease slightly with increasing age. The pharmacokinetics are dose-linear up to dose of 0.4 mL/kg (0.1 mmol/kg), which is times the recommended dose [see Use in Specific Populations (8.4, 8.5, 8.6, and8.7)]. total serum clearance (Cltot) was 250 mL/min, whereas the renal clearance (Clr) corresponds to about 120 mL/min, value similar to the glomerular filtration rate in healthy subjects.MetabolismGadoxetate disodium is not metabolized.

PREGNANCY SECTION.

8.1 Pregnancy Risk Summary GBCAs have been shown to 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 (see Data). In animalreproduction studies, 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 through 18 at doses 26 times the recommended single human dose (see Data). Because of the potential risks of gadolinium to the fetus, use EOVIST only if imaging is essential during pregnancy and cannot be delayed.The background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.. Data Human Data Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration.Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported clear association between GBCAs and adverse effects in the exposed neonates. However, retrospective cohort study, comparing pregnant women who had GBCA MRI to pregnant women who did not have an MRI, reported higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.Animal Data. Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, kidney, and spleen for at least months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age.. Reproductive Toxicology 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.

RECENT MAJOR CHANGES SECTION.

Dosage and Administration (2.2)12/2021. Dosage and Administration (2.2)12/2021.

RISKS.

Risk Summary GBCAs have been shown to 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 (see Data). In animalreproduction studies, 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 through 18 at doses 26 times the recommended single human dose (see Data). Because of the potential risks of gadolinium to the fetus, use EOVIST only if imaging is essential during pregnancy and cannot be delayed.The background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.

SPL MEDGUIDE SECTION.

Medication GuideEOVIST(e-o-vist)(gadoxetate disodium) Injection for intravenous useWhat is EovistoEovist is prescription medicine called gadolinium-based contrast agent (GBCA). Eovist, like other GBCAs, is injected into your vein and used with magnetic resonance imaging (MRI) scanner. oAn MRI exam with GBCA, including Eovist, helps your doctor to see problems better than an MRI exam without GBCA. Eovist is needed to better see the problems in your liver.oYour doctor has reviewed your medical records and has determined that you would benefit from using GBCA with your MRI exam.What is the most important information should know about EovistoEovist contains metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and other parts of your body for long time (several months to years).oIt is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys.oRarely, patients have reported pains, tiredness, and skin, muscle or bone ailments for long time, but these symptoms have not been directly linked to gadolinium.oAt equivalent doses, the amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadavist, or ProHance. oPeople who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.oSome people with kidney problems who get gadolinium medicines can develop condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive Eovist.Do not receive Eovist if you have had severe allergic reaction to Eovist.Before receiving Eovist, tell your healthcare provider about all your medical conditions, including if you:ohave had any MRI procedures in the past where you received GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures.oare pregnant or plan to become pregnant. It is not known if Eovist can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as Eovist is received during pregnancy.ohave kidney problems, diabetes, or high blood pressure. ohave had an allergic reaction to dyes (contrast agents) including GBCAsWhat are the possible side effects of EovistoSee What is the most important information should know about EovistoAllergic reactions. Eovist can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.The most common side effects of Eovist include: nausea, headache, feeling hot, dizziness, and back pain.These are not all the possible side effects of Eovist.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. General information about the safe and effective use of EOVIST.Medicines are sometimes prescribed for purposes other than those listed in Medication Guide. You can ask your healthcare provider for information about EOVIST that is written for health professionals.What are the ingredients in EovistActive ingredient: gadoxetate disodiumInactive ingredients: caloxetate trisodium, trometamol, hydrochloric acid and/or sodium hydroxide (for pH adjustment), and water for injection.Manufactured for Bayer HealthCare Pharmaceuticals Inc.Manufactured in Germany(C) 2008 Bayer HealthCare Pharmaceuticals Inc. All rights reserved.For more information, go to www.eovist.com or call 1-888-842-2937.. oEovist is prescription medicine called gadolinium-based contrast agent (GBCA). Eovist, like other GBCAs, is injected into your vein and used with magnetic resonance imaging (MRI) scanner. oAn MRI exam with GBCA, including Eovist, helps your doctor to see problems better than an MRI exam without GBCA. Eovist is needed to better see the problems in your liver.. oYour doctor has reviewed your medical records and has determined that you would benefit from using GBCA with your MRI exam.. oEovist contains metal called gadolinium. Small amounts of gadolinium can stay in your body including the brain, bones, skin and other parts of your body for long time (several months to years).. oIt is not known how gadolinium may affect you, but so far, studies have not found harmful effects in patients with normal kidneys.. oRarely, patients have reported pains, tiredness, and skin, muscle or bone ailments for long time, but these symptoms have not been directly linked to gadolinium.. oAt equivalent doses, the amount of gadolinium that stays in the body is different for different gadolinium medicines. Gadolinium stays in the body more after Omniscan or Optimark than after Eovist, Magnevist, or MultiHance. Gadolinium stays in the body the least after Dotarem, Gadavist, or ProHance. oPeople who get many doses of gadolinium medicines, women who are pregnant and young children may be at increased risk from gadolinium staying in the body.. oSome people with kidney problems who get gadolinium medicines can develop condition with severe thickening of the skin, muscles and other organs in the body (nephrogenic systemic fibrosis). Your healthcare provider should screen you to see how well your kidneys are working before you receive Eovist.. ohave had any MRI procedures in the past where you received GBCA. Your healthcare provider may ask you for more information including the dates of these MRI procedures.. oare pregnant or plan to become pregnant. It is not known if Eovist can harm your unborn baby. Talk to your healthcare provider about the possible risks to an unborn baby if GBCA such as Eovist is received during pregnancy.. ohave kidney problems, diabetes, or high blood pressure. ohave had an allergic reaction to dyes (contrast agents) including GBCAs. oSee What is the most important information should know about Eovist. oAllergic reactions. Eovist can cause allergic reactions that can sometimes be serious. Your healthcare provider will monitor you closely for symptoms of an allergic reaction.

SPL UNCLASSIFIED SECTION.

2.1Recommended Dose. The recommended dose of EOVIST is 0.1 mL/kg body weight (0.025 mmol/kg body weight).

USE IN SPECIFIC POPULATIONS SECTION.

8USE IN SPECIFIC POPULATIONS. Pregnancy: Use only if imaging is essential during pregnancy and cannot be delayed. (8.1). 8.1 Pregnancy Risk Summary GBCAs have been shown to 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 (see Data). In animalreproduction studies, 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 through 18 at doses 26 times the recommended single human dose (see Data). Because of the potential risks of gadolinium to the fetus, use EOVIST only if imaging is essential during pregnancy and cannot be delayed.The background risk in the U.S. general population of major birth defects is to 4% and of miscarriage is 15 to 20% of clinically recognized pregnancies.. Data Human Data Contrast enhancement is visualized in the placenta and fetal tissues after maternal GBCA administration.Cohort studies and case reports on exposure to GBCAs during pregnancy have not reported clear association between GBCAs and adverse effects in the exposed neonates. However, retrospective cohort study, comparing pregnant women who had GBCA MRI to pregnant women who did not have an MRI, reported higher occurrence of stillbirths and neonatal deaths in the group receiving GBCA MRI. Limitations of this study include lack of comparison with non-contrast MRI and lack of information about the maternal indication for MRI. Overall, these data preclude reliable evaluation of the potential risk of adverse fetal outcomes with the use of GBCAs in pregnancy.Animal Data. Gadolinium Retention GBCAs administered to pregnant non-human primates (0.1 mmol/kg on gestational days 85 and 135) result in measurable gadolinium concentration in the offspring in bone, brain, skin, kidney, and spleen for at least months. GBCAs administered to pregnant mice (2 mmol/kg daily on gestational days 16 through 19) result in measurable gadolinium concentrations in the pups in bone, brain, kidney, liver, blood, muscle, and spleen at one month postnatal age.. Reproductive Toxicology 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.. 8.2 Lactation Risk SummaryThere is no information regarding the presence of gadoxetate disodium in human milk, the effects of the drug in 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 ConsiderationsA 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 breastfed infant.DataAnimal DataIn 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 hours. 8.4Pediatric 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 RiskNo case of NSF associated with EOVIST or any other GBCA has been identified in pediatric patients ages years and younger.Juvenile Animal DataSingle and repeat-dose toxicity studies in neonatal and juvenile rats did not reveal findings suggestive of specific risk for use in pediatric patients including term neonates and infants.. 8.5Geriatric 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 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 group of geriatric volunteers in comparison to non-geriatric volunteers. No clinically relevant differences in liver contrast enhancement were found. 8.6Renal Impairment. In clinical pharmacology study in group of patients with moderate renal impairment, 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 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 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 days, predominantly within the first days.. 8.7Hepatic Impairment. In clinical pharmacology study in groups of patients with mild or moderate hepatic impairment, 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 (> 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 diagnosis of liver cirrhosis (Child-Pugh category A, = 270; category B, = 98; category C, = 24; unknown category, = 97). No difference in diagnostic performance and safety was observed among these patients.

WARNINGS AND PRECAUTIONS SECTION.

5WARNINGS AND PRECAUTIONS. oNephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk (5.1)oHypersensitivity: 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 (5.2)oGadolinium is retained for months or years in brain, bone, and other organs. (5.3). oNephrogenic Systemic Fibrosis has occurred in patients with impaired elimination of GBCAs. Higher than recommended dosing or repeated dosing appears to increase the risk (5.1). oHypersensitivity: 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 (5.2). oGadolinium is retained for months or years in brain, bone, and other organs. (5.3). 5.1Nephrogenic 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 GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to patient. For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow 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 GBCA in order to enhance the contrast agents elimination [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. The usefulness of hemodialysis in the prevention of NSF is unknown.. 5.2Hypersensitivity 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)].oBefore EOVIST administration, assess all patients for any history of reaction to contrast media, bronchial asthma and allergic disorders. These patients may have an increased risk for hypersensitivity reaction to EOVIST.oAdminister 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. oBefore EOVIST administration, assess all patients for any history of reaction to contrast media, bronchial asthma and allergic disorders. These patients may have an increased risk for hypersensitivity reaction to EOVIST.. oAdminister EOVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.. 5.3Gadolinium Retention Gadolinium is retained for months or years in several organs. The highest concentrations (nanomoles per gram of tissue) have been identified in the bone, followed by other organs (for example, 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. At equivalent doses, gadolinium retention varies among the linear agents with Omniscan (gadodiamide) and Optimark (gadoversetamide) causing greater retention than other linear agents [Eovist (gadoxetate disodium), Magnevist (gadopentetate dimeglumine),MultiHance (gadobenate dimeglumine)]. Retention is lowest and similar among the macrocyclic GBCAs [Dotarem (gadoterate meglumine), Gadavist (gadobutrol), ProHance (gadoteridol)]. Consequences of gadolinium retention in the brain have not been established. Pathologic and clinical consequences of GBCA administration and retention in skin and other organs have been established in patients with impaired renal function [see Warnings and Precautions (5.1)]. There are rare reports of pathologic skin changes in patients with normal renal function. Adverse events involving multiple organ systems have been reported in patients with normal renal function without an established causal link to gadolinium retention [see Adverse Reactions (6.2)].While clinical consequences of gadolinium retention have not been established in patients with normal renal function, certain patients might be at higher risk. These include patients requiring multiple lifetime doses, pregnant and pediatric patients, and patients with inflammatory conditions. Consider the retention characteristics of the agent when choosing GBCA for these patients. Minimize repetitive GBCA imaging studies particularly closely spaced studies, when possible.. 5.4Acute 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.. 5.5Extravasation 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)].. 5.6Interference 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)].. 5.7Interference 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 paired non-contrast and contrast MRI set for diagnosis.