EOVIST (Page 4 of 5)

10 OVERDOSAGE

The maximum dose studied in MR imaging was 0.4 mL/kg (0.1 mmol/kg) body weight and was tolerated in a 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)].

11 DESCRIPTION

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 GdC23 H28 N3 O11 Na2 . The structural formula of gadoxetate disodium in aqueous solution is:

Structure
(click image for full-size original)

Each mL of EOVIST contains 181.43 mg of gadoxetate disodium (equivalent to 0.25 mmol/mL gadoxetate disodium) and the excipients caloxetate trisodium, 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 H2 O)

0.688

Viscosity at 37°C (cP)

1.19

Density at 37°C (g/mL)

1.088

pH

6.8-8

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Gadoxetate disodium is a paramagnetic compound and develops a magnetic moment when placed in a magnetic field. The relatively large magnetic moment produced by gadoxetate disodium results in a 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 a 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.

12.2 Pharmacodynamics

EOB-DTPA forms a stable complex with the paramagnetic gadolinium ion with a thermodynamic stability of log KGdL=‑23.46. Gadoxetate disodium is a highly water-soluble, hydrophilic compound with a lipophilic moiety, the ethoxybenzyl group (EOB). Gadoxetate disodium shows a weak (<10%), transient protein binding and the relaxivity in plasma is about 8.7 L/mmol/sec at pH 7, 39°C 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 a biphasic mode of action: first, distribution in the extracellular space after bolus injection and subsequently, selective uptake by hepatocytes (and biliary excretion) due to the lipophilic (EOB) moiety.

12.3 Pharmacokinetics

Distribution

After intravenous administration, the plasma concentration time profile of gadoxetate disodium is characterized by a 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)].

Elimination

Gadoxetate 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 a dose of 0.4 mL/kg (0.1 mmol/kg), which is 4 times the recommended dose [see Use in Specific Populations (8.4, 8.5, 8.6, and 8.7)].

A total serum clearance (Cltot ) was 250 mL/min, whereas the renal clearance (Clr ) corresponds to about 120 mL/min, a value similar to the glomerular filtration rate in healthy subjects.

Metabolism

Gadoxetate disodium is not metabolized.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, 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 4 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

A dose-related increase in QTc which was resolved by 30 minutes post dosing was observed in dogs when given a 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 1 of 3 mice when given EOVIST at a dose of approximately 1.1 mmol/kg (3.6 times the human dose); the disturbance occurred at 30 minutes post dosing and resolved at 4 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)].

14 CLINICAL 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 1 and 2) or morphological characterization (studies 3 and 4) of liver lesions. Studies 1 and 2 (“detection” studies) enrolled patients who were scheduled for liver surgery. MRI results were compared to a 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 3 and 4 (“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 a 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 a baseline, pre-contrast MRI followed by the administration of EOVIST at a 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 a systematic, randomized, paired and unpaired fashion by three radiologists who were blinded to clinical information. CT images were also evaluated by the radiologists in a 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 3 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 3 Sensitivity in Liver Lesion Detection

Diagnostic Procedure

Reader

Study 1Sensitivity (%)n=129

Study 2Sensitivity (%)n=126

Pre-contrast MRI

Reader 1

76

77

Reader 2

76

73

Reader 3

71

72

Combined pre- and EOVIST-contrast MRI

Reader 1

81

82

Reader 2

78

76

Reader 3

74

78

Difference:

combined pre + EOVIST-contrast MRI minus pre MRI

(95% confidence interval)

Reader 1

5 (1, 9)*

5 (1, 9)*

Reader 2

2 (-1, 5)

3 (-1, 7)

Reader 3

3 (0, 6)*

6 (0, 10)*

* Statistically significant improvement

Table 4 Proportion of Correctly Characterized Lesions

Study 3

Study 4

Diagnostic Procedure

Reader

n

Proportion correct (%) **

n

Proportion correct (%) **

Pre-contrast MRI

Reader 1

182

51

177

60

Reader 2

182

59

177

64

Reader 3

182

53

177

48

Combined pre- and EOVIST-contrast MRI

Reader 1

182

67

177

61

Reader 2

182

76

177

76

Reader 3

182

58

177

67

Difference: combined pre- and EOVIST-contrast MRI minuspre-contrast MRI

(95% confidence interval)

Reader 1

16 (7, 25)*

1 (-7, 10)

Reader 2

17 (9, 25)*

11 (5, 18)*

Reader 3

5 (-2, 12)

19 (11, 27)*

* Statistically significant improvement

** Proportion of correctly characterized lesions with respect to the reference

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