Gadoxetate Disodium

Prescription

Handelsnamen: EOVIST

Darreichungsform

Injection

Applikationsweg

INTRAVENOUS

Hersteller

Bayer HealthCare Pharmaceuticals Inc.

About This Medication

11 DESCRIPTION EOVIST (gadoxetate disodium) injection is a paramagnetic gadolinium-based contrast agent for intravenous use. Gadoxetate disodium (Gd-EOB-DTPA) is a highly water-soluble, hydrophilic compound with a lipophilic moiety, the ethoxybenzyl group (EOB). EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with a thermodynamic stability of log KGdL=-23.46. 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 a molecular weight of 725.72 and an empirical formula of GdC 23 H 28 N 3 O 11 Na 2 . The structural formula of gadoxetate disodium is: EOVIST is a sterile, clear, colorless to pale yellow solution. Each mL contains 181.43 mg (0.25 mmol) of gadoxetate disodium (containing 0.25 mmol of gadolinium) and the following inactive ingredients: 1 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 2: Physicochemical Properties of EOVIST Parameter Value Osmolality at 37°C (Osm/kg H 2 O) 0.688 Viscosity at 37°C (cP) 1.19 Density at 37°C (g/mL) 1.088 pH 6.8-8 Chemical Structure

Wirkstoffe

Wirkstoff	Stärke
Gadoxetate Disodium	-

Indikationen und Anwendung

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

So funktioniert es

12.1 Mechanism of Action Gadoxetate is a paramagnetic molecule that develops a magnetic moment when placed in a magnetic field. The magnetic moment alters the relaxation rates of water protons in its vicinity in the body, leading to an increase in signal intensity (brightness) of tissues. Gadoxetate is selectively taken up by hepatocytes, resulting in increased signal intensity in liver tissue.

Dosierung und Verabreichung

2 DOSAGE AND ADMINISTRATION Recommended dose is 0.025 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered by intravenous injection at 1 mL/sec to 2 mL/sec. ( 2.1 ) See Full Prescribing Information for administration and imaging instructions. ( 2.2 , 2.3 ) 2.1 Recommended Dose The recommended dose of EOVIST for adult and pediatric patients, including term neonates, is 0.025 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered intravenously at a recommended rate of 1 mL/sec to 2 mL/sec. 2.2 Administration and Drug Handling EOVIST is for intravenous use only and must not be administered intrathecally [see Warnings and Precautions (5.1) ]. Use aseptic technique when preparing and administering EOVIST. 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. Use EOVIST immediately after obtaining appropriate dose from vial. Pierce the rubber stopper only once. Discard any unused portion of an EOVIST vial. 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 0.9% Sodium Chloride Injection after EOVIST injection. 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 seconds to 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 (5.8) 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.

Side Effects Overview

6 ADVERSE REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling: Nephrogenic systemic fibrosis [see Warnings and Precautions (5.2) ] Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥ 0.5%) are nausea, headache, feeling hot, dizziness, and back pain. ( 6.1 ) 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. 6.1 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. Adverse Reactions in Adults The safety of EOVIST was evaluated in 1,989 adult subjects who received EOVIST in clinical trials. Overall, 59% of the subjects were male, and the racial and ethnic distribution was 64% White, 22% Asian, 3% Hispanic or Latino, 2% Black or African American, and 0.5% other ethnic groups. The average age was 57 years (age range from 19 to 84 years). Table 1 lists adverse reactions that occurred in ≥ 0.1% of subjects who received the recommended dose of EOVIST in clinical trials. Table 1: Adverse Reactions Reported in ≥ 0.1% of Adult Subjects who Received EOVIST in Clinical Trials Adverse Reaction EOVIST n = 1,581 Rate (%) Nausea 1.1 Headache 1.1 Feeling hot 0.8 Dizziness 0.6 Back pain 0.6 Vomiting 0.4 Blood pressure increased 0.4 Injection site reactions (pain, burning, coldness, extravasation, irritation) 0.4 Dysgeusia 0.4 Paresthesia 0.3 Flushing 0.3 Parosmia 0.3 Pruritus (generalized, eye) 0.3 Rash 0.3 Respiratory disorders (dyspnea, respiratory distress) 0.2 Fatigue 0.2 Chest pain 0.1 Vertigo 0.1 Dry mouth 0.1 Chills 0.1 Feeling abnormal 0.1 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 < 1% of subjects 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. Adverse Reactions in Pediatric Patients In a study of EOVIST in 52 pediatric patients between 2 months of age and 18 years of age, no new safety signals were observed [see Use in Specific Populations (8.4) ]. 6.2 Postmarketing Experience The following additional adverse reactions have been identified during the postmarketing use of EOVIST or other GBCAs. 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. Cardiac Disorders: Tachycardia Gastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration General Disorders and Administration Site Conditions: Fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems with variable onset and duration after GBCA administration [see Warnings and Precautions (5.4) ] Immune System Disorders: Hypersensitivity reactions (anaphylactic shock, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough and pallor) Psychiatric Disorders: Restlessness Renal Disorders: Nephrogenic systemic fibrosis Respiratory, Thoracic, and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema Skin Disorders: Gadolinium associated plaques

Warnhinweise und Vorsichtsmaßnahmen

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Anaphylactic and other 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 ( 5.3 ) Gadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.4 ) 5.1 Risk Associated with Intrathecal Use Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety and effectiveness of EOVIST have not been established with intrathecal use. EOVIST is not approved for intrathecal use [see Dosage and Administration (2.2) ]. 5.2 Nephrogenic Systemic Fibrosis GBCAs increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of EOVIST 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/1.73m 2 ) 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/1.73m 2 ) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m 2 ). 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, 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. 5.3 Hypersensitivity Reactions Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe, including shock have occurred following EOVIST administration. Most hypersensitivity reactions to EOVIST have occurred within half an hour after administration. Delayed reactions can occur up to several days after EOVIST administration [see Adverse Reactions (6.2) ] . 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. EOVIST is contraindicated in patients with history of hypersensitivity reactions to EOVIST [see Contraindications (4) ]. Administer EOVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. Observe patients for signs and symptoms of hypersensitivity reactions during and following EOVIST administration. 5.4 Gadolinium 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 gadodiamide causing greater retention than other linear agents such as gadoxetate disodium and gadobenate dimeglumine. Retention is lowest and similar among the macrocyclic GBCAs such as gadoterate meglumine, gadobutrol, gadoteridol, and gadopiclenol. 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 (5.2) ] . 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 a GBCA for these patients. Minimize repetitive GBCA imaging studies particularly closely spaced studies, when possible. 5.5 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. 5.6 Extravasation and Injection Site Reactions Injection site reactions such as pain have been reported in clinical studies with EOVIST [see Adverse Reactions (6.1) ]. Extravasation into tissues during EOVIST administration may result in local tissue reactions such as myocyte necrosis and inflammation [see Nonclinical Toxicology (13.2) ] . Ensure catheter and venous patency before the injection of EOVIST. 5.7 Interference with Laboratory Tests EOVIST can interfere with serum iron determination using complexometric methods (for example, ferrocene complexation method) [see Drug Interactions (7) ]. 5.8 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 [see Dosage and Administration (2.3) ] .

Kontraindikationen

4 CONTRAINDICATIONS EOVIST is contraindicated in patients with history of severe hypersensitivity reactions to EOVIST [see Warnings and Precautions (5.3) ] . History of severe hypersensitivity reaction to EOVIST ( 4 )

Pharmakokinetik

12.3 Pharmacokinetics Distribution Gadoxetate exhibits a 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. After intravenous administration, the plasma concentration time profile of gadoxetate is characterized by a bi-exponential decline. The total distribution volume of gadoxetate 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 (5.4) ]. Elimination The mean terminal elimination half-life of gadoxetate (0.01 to 0.1 mmol/kg) has been observed in healthy subjects of 22 to 39 years of age to be 0.91 to 0.95 hour. The pharmacokinetics are dose-linear up to a dose of 0.1 mmol/kg (4 times the recommended dose) . A total serum clearance (Cl tot ) was 250 mL/min, whereas the renal clearance (Cl r ) corresponds to about 120 mL/min, a value similar to the glomerular filtration rate in healthy subjects. Metabolism Gadoxetate is not metabolized. Excretion Gadoxetate is equally eliminated via the renal and hepatobiliary routes. Specific Populations Geriatric Patients In a clinical pharmacology study, the AUC and terminal half-life of gadoxetate were slightly increased (1.2-fold and 1.3-fold, respectively) and total clearance was decreased by 0.8-fold in geriatric patients compared to non-geriatric patients. Patients with Renal Impairment In a study of patients with end-stage renal failure, the AUC was increased about 6-fold and the terminal half-life was prolonged about 12-fold. Approximately 30% of the injected dose was removed by dialysis in a single 3-hour dialysis session, which started 1 hour after an EOVIST dose. Gadoxetate was almost completely eliminated via hemodialysis and biliary excretion within the observation period of 6 days, predominantly within the first 3 days [see Use in Specific Populations (8.6) ] . In patients with moderate renal impairment, a moderate increase in AUC and terminal half-life (1.5-fold and 1.2-fold, respectively) was observed in comparison to healthy subjects with normal renal function. Patients with Hepatic Impairment In patients with severe hepatic impairment, especially in patients with abnormally high (> 3 mg/dL) serum bilirubin levels, the AUC of gadoxetate 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 [see Use in Specific Populations (8.7) ] . In patients with mild or moderate hepatic impairment, a slight to moderate increase in plasma AUC (1.6-fold), half-life (1.1-fold), and urinary excretion (1.3-fold), as well as decrease in hepatobiliary excretion (0.7-fold) was observed in comparison to healthy subjects with normal liver function.

Frequently Asked Questions

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

2 DOSAGE AND ADMINISTRATION Recommended dose is 0.025 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered by intravenous injection at 1 mL/sec to 2 mL/sec. ( 2.1 ) See Full Prescribing Information for administration and imaging instructions. ( 2.2 , 2.3 ) 2.1 Recommended Dose The recommended dose of EOVIST for adult and pediatric patients, including term neonates, is 0.025 mmol/kg actual body weight (equivalent to 0.1 mL/kg) administered intravenously at a recommended rate of 1 mL/sec to 2 …

5 WARNINGS AND PRECAUTIONS Hypersensitivity Reactions: Anaphylactic and other 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 ( 5.3 ) Gadolinium Retention: Gadolinium is retained for months or years in brain, bone, and other organs. ( 5.4 ) 5.1 Risk Associated with Intrathecal Use Intrathecal administration of GBCAs can cause serious adverse reactions including death, coma, encephalopathy, and seizures. The safety …

4 CONTRAINDICATIONS EOVIST is contraindicated in patients with history of severe hypersensitivity reactions to EOVIST [see Warnings and Precautions (5.3) ] . History of severe hypersensitivity reaction to EOVIST ( 4 )

Gadoxetate Disodium is a prescription medication. You will need a valid prescription from a licensed healthcare provider.

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References & Data Sources

• DailyMed — Gadoxetate Disodium drug label (National Library of Medicine)
• openFDA — Gadoxetate Disodium label data (U.S. Food & Drug Administration)
• NDC Directory — Gadoxetate Disodium (FDA National Drug Code)

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