GADOXETATE: 435 Adverse Event Reports & Safety Profile

EOVIST (gadoxetate disodium) is a paramagnetic contrast agent administered for MRI. EOVIST is provided as a 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 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 in aqueous solution is: Each mL of EOVIST contains 181.43 mg (0.25 mmol) of gadoxetate 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

2 Physicochemical Properties 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 Structure

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 a 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 )

• Recommended dose is 0.1 mL/kg body weight ( 2.1 )
• Administer as an intravenous injection at a recommended rate of 1 mL to 2 mL per second ( 2.2 )
• Follow injection with a normal saline flush ( 2.2 )

2.2 Drug Handling and Administration

• Use sterile technique when preparing and administering EOVIST
• Visually inspect EOVIST, supplied in a 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
• Use EOVIST immediately after obtaining appropriate dose from vial. The rubber stopper should never be pierced more than once. Discard any unused portion of an EOVIST vial
• Administer EOVIST undiluted as an intravenous injection at a recommended rate of 1 mL to 2 mL per second.
• Do not mix EOVIST with other medications and do not administer EOVIST in the same intravenous line simultaneously with other medications
• Flush the intravenous cannula with a normal saline solution after EOVIST injection
• Imaging can commence immediately following EOVIST administration

2.3 Imaging

• Liver lesions are detected and characterized with pre-contrast MRI and EOVIST MRI obtained during dynamic and hepatocyte imaging phases. Perform a pre-contrast MRI, inject EOVIST and begin dynamic imaging approximately 15–25 seconds after completion of the injection. Dynamic imaging consists of the arterial, the porto-venous (approximately 60 seconds post-injection), and the blood equilibrium (approximately 120 seconds) phases.
• Begin the hepatocyte imaging phase approximately 20 minutes post-injection. Hepatocyte phase imaging may be performed up to 120 minutes post-injection.
• Elevated intrinsic levels of bilirubin (>3 mg/dL) or ferritin can reduce the hepatic contrast effect of EOVIST. Perform MR imaging no later than 60 minutes following EOVIST administration to patients with these laboratory abnormalities, including patients who have elevated ferritin levels due to hemodialysis [see Warnings and Precautions ( 5.7 ) 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.

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 )

REACTIONS The following clinically significant adverse reactions are discussed elsewhere in the labeling:

• Nephrogenic systemic fibrosis (NSF) [see Boxed Warning and Warnings and Precautions ( 5.2 )]
• Hypersensitivity reactions [see Contraindications ( 4 ) and Warnings and Precautions ( 5.3 )]
• Gadolinium Retention [see Warnings and Precautions (5.4)] 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.

6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. The adverse reactions described in this section reflect EOVIST exposure in 1,989 subjects with the majority (1,581 subjects) receiving the recommended dose. Overall, 59% of the subjects were men and the ethnic distribution was 64% Caucasian, 22% Asian, 3% Hispanic, 2% Black, and 0.5% of subjects consisted of other ethnic groups. The average age was 57 years (age range from 19 to 84 years). Overall, 4% of subjects reported one or more adverse reactions following EOVIST administration. The most frequent (≥ 0.5%) adverse reactions associated with the use of EOVIST were nausea, headache, feeling hot, dizziness, and back pain. Adverse reactions were predominantly of mild to moderate severity.

Table

1 lists adverse reactions that occurred in ≥ 0.1% of subjects treated with EOVIST.

Table

1 Adverse Reactions Reaction Rate (%) n = 1581 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 less than 1% of patients after administration of EOVIST. The values did not exceed more than 3 times the baseline values and returned to baseline within 1 to 4 days.

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.

• Hypersensitivity reactions (anaphylactic shock, hypotension, pharyngolaryngeal edema, urticaria, face edema, rhinitis, conjunctivitis, abdominal pain, hypoesthesia, sneezing, cough and pallor)
• Respiratory, Thoracic, and Mediastinal Disorders: Acute respiratory distress syndrome, pulmonary edema
• Tachycardia
• Restlessness
• General Disorders and Administration Site Conditions: Adverse reactions with variable onset and duration have been reported after GBCA administration. These include fatigue, asthenia, pain syndromes, and heterogeneous clusters of symptoms in the neurological, cutaneous, and musculoskeletal systems .
• Skin: Gadolinium associated plaques
• Gastrointestinal Disorders: Acute pancreatitis with onset within 48 hours after GBCA administration

AND PRECAUTIONS

• Hypersensitivity Reactions: 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 ( 5.3 )
• 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 <span class="opacity-50 text-xs">[see Dosage and Administration ( 2.2 )]</span>.

5.2 Nephrogenic Systemic Fibrosis (NSF) 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 &lt; 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 &gt; 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing. Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to a patient. For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow a sufficient period of time for elimination of the drug prior to any re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination <span class="opacity-50 text-xs">[see Use in Specific Populations ( 8.6 ) and Clinical Pharmacology ( 12.3 )]</span>. 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 uncommonly occurred following EOVIST administration <span class="opacity-50 text-xs">[see Adverse Reactions ( 6 )]</span> .

• Before EOVIST administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to EOVIST.
• Administer EOVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation. Most hypersensitivity reactions to EOVIST have occurred within half an hour after administration. Delayed reactions can occur up to several days after EOVIST administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following EOVIST administration.

5.4 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 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 <span class="opacity-50 text-xs">[see Warnings and Precautions ( 5.2 )]</span> . 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 <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.2 )]</span> . 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 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 <span class="opacity-50 text-xs">[see Nonclinical Toxicology ( 13.2 )]</span> .

5.7 Interference with Laboratory Tests Serum iron determination using complexometric methods (for example, ferrocene complexation method) may result in falsely high or low values for up to 24 hours after the examination with EOVIST because of the caloxetate trisodium excipients <span class="opacity-50 text-xs">[see Adverse Reactions ( 6.1 )]</span> .

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 (&gt;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.