EOVIST: Package Insert and Label Information

EOVIST- gadoxetate disodium injection, solution
Bayer HealthCare Pharmaceuticals Inc.

WARNING: NEPHROGENIC SYSTEMIC FIBROSIS (NSF)

Gadolinium-based contrast agents (GBCAs) increase the risk for NSF among patients with impaired elimination of the drugs. Avoid use of GBCAs in these patients unless the diagnostic information is essential and not available with non-contrasted MRI or other modalities. NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs.

The risk for NSF appears highest among patients with:
o
Chronic, severe kidney disease (GFR < 30 mL/min/1.73m2), or
o
Acute kidney injury.
Screen patients for acute kidney injury and other conditions that may reduce renal function. For patients at risk for chronically reduced renal function (for example, age > 60 years, hypertension or diabetes), estimate the glomerular filtration rate (GFR) through laboratory testing.

For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow a sufficient period of time for elimination of the drug from the body prior to any re-administration [see Warnings and Precautions (5.1)].

1 INDICATIONS 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.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dose

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

2.2 Drug Handling and Administration

Use sterile technique when preparing and administering EOVIST
Visually inspect EOVIST, supplied in a single-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 bolus injection at a flow rate of approximately 2 mL/second
Do not mix EOVIST with other medications and do not administer EOVIST in the same intravenous line simultaneously with other medications
Flush the intravenous cannula with a normal saline solution after EOVIST injection
Imaging can commence immediately following EOVIST administration

2.3 Imaging

Liver lesions are detected and characterized with pre-contrast MRI and EOVIST MRI obtained during dynamic and hepatocyte imaging phases. Perform a pre-contrast MRI, inject EOVIST and begin dynamic imaging approximately 15–25 seconds after completion of the injection. Dynamic imaging consists of the arterial, the porto-venous (approximately 60 seconds post-injection), and the blood equilibrium (approximately 120 seconds) phases.
Begin the hepatocyte imaging phase approximately 20 minutes post-injection. Hepatocyte phase imaging may be performed up to 120 minutes post-injection.
Elevated intrinsic levels of bilirubin (>3 mg/dL) or ferritin can reduce the hepatic contrast effect of EOVIST. Perform MR imaging no later than 60 minutes following EOVIST administration to patients with these laboratory abnormalities, including patients who have elevated ferritin levels due to hemodialysis [see Warnings and Precautions (5.6) and Use in Specific Populations (8.6, 8.7)].
Lesions with no or minimal hepatocyte function (cysts, metastases, and the majority of hepatocellular carcinomas) generally will not accumulate EOVIST. Well-differentiated hepatocellular carcinoma may contain functioning hepatocytes and can show some enhancement in the hepatocyte imaging phase. Additional clinical information is therefore needed to support a diagnosis of hepatocellular carcinoma.

3 DOSAGE FORMS AND STRENGTHS

EOVIST is a 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).

4 CONTRAINDICATIONS

EOVIST is contraindicated in patients with history of severe hypersensitivity reactions to EOVIST.

5 WARNINGS AND PRECAUTIONS

5.1 Nephrogenic Systemic Fibrosis (NSF)

Gadolinium-based contrast agents (GBCAs) increase the risk for nephrogenic systemic fibrosis (NSF) among patients with impaired elimination of the drugs. Avoid use of GBCAs among these patients unless the diagnostic information is essential and not available with non-contrast enhanced MRI or other modalities. The GBCA-associated NSF risk appears highest for patients with chronic, severe kidney disease (GFR < 30 mL/min/1.73m2) as well as patients with acute kidney injury. The risk appears lower for patients with chronic, moderate kidney disease (GFR 30 to 59 mL/min/1.73m2) and little, if any, for patients with chronic, mild kidney disease (GFR 60 to 89 mL/min/1.73m2). NSF may result in fatal or debilitating fibrosis affecting the skin, muscle and internal organs. Report any diagnosis of NSF following EOVIST administration to Bayer HealthCare (1-888-842-2937) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch).

Screen patients for acute kidney injury and other conditions that may reduce renal function. Features of acute kidney injury consist of rapid (over hours to days) and usually reversible decrease in kidney function, commonly in the setting of surgery, severe infection, injury or drug-induced kidney toxicity. Serum creatinine levels and estimated GFR may not reliably assess renal function in the setting of acute kidney injury. For patients at risk for chronically reduced renal function (for example, age > 60 years, diabetes mellitus or chronic hypertension), estimate the GFR through laboratory testing.

Among the factors that may increase the risk for NSF are repeated or higher than recommended doses of a GBCA and degree of renal impairment at the time of exposure. Record the specific GBCA and the dose administrated to a patient. For patients at highest risk for NSF, do not exceed the recommended EOVIST dose and allow a sufficient period of time for elimination of the drug prior to any re-administration. For patients receiving hemodialysis, physicians may consider the prompt initiation of hemodialysis following the administration of a GBCA in order to enhance the contrast agent’s elimination [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)]. The usefulness of hemodialysis in the prevention of NSF is unknown.

5.2 Hypersensitivity Reactions

Anaphylactic and other hypersensitivity reactions with cardiovascular, respiratory and cutaneous manifestations, ranging from mild to severe, including shock have uncommonly occurred following EOVIST administration [see Adverse Reactions (6)].

Before EOVIST administration, assess all patients for any history of a reaction to contrast media, bronchial asthma and allergic disorders. These patients may have an increased risk for a hypersensitivity reaction to EOVIST.
Administer EOVIST only in situations where trained personnel and therapies are promptly available for the treatment of hypersensitivity reactions, including personnel trained in resuscitation.

Most hypersensitivity reactions to EOVIST have occurred within half an hour after administration. Delayed reactions can occur up to several days after EOVIST administration. Observe patients for signs and symptoms of hypersensitivity reactions during and following EOVIST administration.

5.3 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 [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 a GBCA for these patients. Minimize repetitive GBCA imaging studies particularly closely spaced studies, when possible.

5.4 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.

5.5 Extravasation and Injection Site Reactions

Ensure catheter and venous patency before the injection of EOVIST. Extravasation into tissues during EOVIST administration may result in local tissue reactions. Strictly avoid intramuscular administration of EOVIST because it may cause myocyte necrosis and inflammation [see Nonclinical Toxicology (13.2)].

5.6 Interference with Laboratory Tests

Serum iron determination using complexometric methods (for example, ferrocene complexation method) may result in falsely high or low values for up to 24 hours after the examination with EOVIST because of the caloxetate trisodium excipients [see Adverse Reactions (6.1)].

5.7 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.

6 ADVERSE REACTIONS

The following serious adverse reactions are discussed elsewhere in the labeling:

Nephrogenic systemic fibrosis (NSF) [see Boxed Warning and Warnings and Precautions (5.1)]
Hypersensitivity reactions [see Contraindications (4) and Warnings and Precautions (5.2)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

The adverse reactions described in this section reflect EOVIST exposure in 1,989 subjects with the majority (1,581 subjects) receiving the recommended dose. Overall, 59% of the subjects were men and the ethnic distribution was 64% Caucasian, 22% Asian, 3% Hispanic, 2% Black, and 0.5% of subjects consisted of other ethnic groups. The average age was 57 years (age range from 19 to 84 years).

Overall, 4% of subjects reported one or more adverse reactions following EOVIST administration. The most frequent (≥ 0.5%) adverse reactions associated with the use of EOVIST were nausea, headache, feeling hot, dizziness, and back pain. Adverse reactions were predominantly of mild to moderate severity.

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

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.

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