Feridex I.V.

CLINICAL PHARMACOLOGY

General

Feridex I.V. (ferumoxides injectable solution) is an intravenously injected colloidal superparamagnetic iron oxide associated with dextran. It is a magnetic resonance imaging (MRI) contrast agent and is taken up by cells of the reticuloendothelial system (RES).

Pharmacokinetics

Three healthy, adult male volunteers received a dose of Feridex I.V. (ferumoxides injectable solution) 0.56 mg of Fe/kg (diluted in 100 mL of 5% dextrose and intravenously infused over 30 minutes). In these subjects, the mean ± SD peak serum iron concentration was 5.5 ± 0.6 μg/mL, elimination half-life was 2.4 ± 0.2 hours and total clearance 28.5 ± 1.6 mL/min. Feridex I.V. (ferumoxides injectable solution) was completely cleared from the blood by 25 hours after administration. Less than 2% of the drug was excreted in the urine, as expected for iron.

At 24 hours, serum iron increased and the percent saturation of iron binding capacity decreased in a dose-dependent fashion. By 7 days, serum iron returned to pre-administration levels, and serum ferritin increased. These results are consistent with the iron in Feridex I.V. (ferumoxides injectable solution) entering the usual iron metabolism cycle. Animal pharmacokinetics studies were consistent with these results in humans.

Imaging studies in rats showed a large decrease in liver signal intensity for the first 24 hours after dosing, followed by a gradual return to normal over 7 days. Radiotracer studies in rats were consistent with the iron in Feridex I.V. (ferumoxides injectable solution) becoming part of the body iron pool. Histological studies in rats showed that the iron was in the RES and that it disappeared from the RES over 7 to 14 days with all evidence of iron gone by 14–28 days.

In human clinical studies, there was no difference in loss of signal intensity on images obtained between 0–3.5 hours after infusion. Loss of signal intensity decreased at 1 and 2 days.

Metabolism

The iron in Feridex I.V. (ferumoxides injectable solution) enters the normal body iron metabolism cycle as evidenced by transient increases in serum iron values one day after administration and increase in serum ferritin values 7 days after administration. The amount of iron contained in a single dose is 39 mg for a 70 kg individual. This is less than 1/5 the amount of iron contained in one unit of whole blood.

Special Populations

Geriatric/Pediatric: Pharmacokinetics in these populations were not studied. Patients enrolled in clinical trials were between 11 and 89 years old.

Gender: Women showed a higher pre-contrast signal intensity and hence a larger decrease in liver signal intensity in images. This is consistent with a lower baseline iron in women.

Race: Differences due to race were not noted.

Renal Insufficiency: Feridex I.V. (ferumoxides injectable solution) is not renally cleared; no studies were performed in patients with renal insufficiency.

Hepatic Insufficiency: Patients with cirrhosis had less of a decrease in liver signal intensity than other patients with known or suspected liver lesions. Patients with cirrhosis also had a higher incidence of back pain. (See ADVERSE REACTIONS section.)

Hemochromatosis: Individuals with iron overload were not studied. Feridex I.V. (ferumoxides injectable solution) contains iron. Literature reports suggested that Feridex I.V. (ferumoxides injectable solution) will not add information to their MRI evaluations, since iron overload causes loss in liver signal intensity.

Drug-Drug Interactions

In rats, the simultaneous administration of heparin was found to prolong the half-life of Feridex I.V. (ferumoxides injectable solution) in the blood. The effects of Feridex I.V. (ferumoxides injectable solution) administration on heparin anticoagulation are not known.

Pharmacodynamics

Feridex I.V. (ferumoxides injectable solution) shortens the relaxation times for nearby hydrogen atoms and reduces signal intensity in normal tissues. This results in signal loss (image darkening) on mid T1/T2 or strongly T2-weighted images. Tissues with decreased RES function (e.g., metastases, primary liver cancer, cysts and various benign tumors, adenomas, and hyperplasia) retain their native signal intensity, so the contrast between normal and abnormal tissue is increased.

Clinical Trials

Two clinical studies evaluated a total of 211 patients, (107 men and 104 women, 22–83 years of age) with a variety of known or suspected liver lesions. Of these patients, efficacy evaluations were completed on 96 patients in Study A, and 112 patients in Study B. At baseline, patients had a CECT (contrast enhanced computerized tomography) scan with any iodinated contrast agent and a noncontrast MRI (magnetic resonance imaging) within 24 hours before Feridex I.V. (ferumoxides injectable solution) administration. Feridex I.V. (ferumoxides injectable solution) (0.56 mg/kg) was administered intravenously over 30 minutes. Images were acquired up to 3.5 hours after the end of the infusion. The CECT, unenhanced MRI, and Feridex I.V. (ferumoxides injectable solution) enhanced MRI images were read blindly (i.e., by radiologists who were not told of the patient's medical history or the presence of image contrast enhancing drugs). Results from blindly read images were compared to the final clinical diagnosis. The final clinical diagnoses were confirmed with histopathologic, surgical, or biopsy findings in 86 (41%) of patients. MRI scans were evaluated for the quantitative analysis of signal intensity in liver lesion(s), and by blinded evaluations of the resulting images for changes in number and location of lesions, delineation of lesion margins, presence or absence of lesions, and characterization of lesions.

Based upon these two studies, Feridex I.V. (ferumoxides injectable solution) reduced the signal intensity of normal liver on T2 weighted pulse sequences to improve MRI contrast. Contrast to noise ratios were increased on T2 images and decreased on T1 images. Image interpretations for contrast enhancement, the number of lesions identified, and the sensitivity and specificity of the determination of whether an abnormal lesion was present are shown in the following table. The mean number of lesions seen before and after Feridex I.V. (ferumoxides injectable solution) were comparable. The majority of new lesions (86%) were 0.5 cm–1.0 cm in size, but other lesions were seen that were < 0.5 cm or > 1.0 cm.

IMAGE INTERPRETATION RESULTS AFTER UNENHANCED MRI, CECT** AND FERIDEX I.V. (ferumoxides injectable solution) ENHANCED MRI IN TWO CLINICAL STUDIES OF PATIENTS WITH KNOWN OR SUSPECTED LIVER LESIONS

Outcome Measure Control Comparisons Study A
(N = 96)
Study B
(N=112)
Contrast between normal and abnormal liver tissue seen on MRI MRI Contrast Better with Feridex I.V. 84% 86%
MRI Contrast Same with Feridex I.V. 13% 12%
MRI Contrast Worse with Feridex I.V. 3% 2%
(p < 0.01) (p < 0.01)
Number of Patients with Lesions Seen on MRI Patients with:  
  More before Feridex I.V. 13% 21%
  Same before and after Feridex I.V. 62% 51%
  More After Feridex I.V 25% 28%
Number of liver lesions seen on MRI(Mean ± SD) MRI before Feridex I.V. after Feridex I.V. 7.3 ± 15.9 6.7 ± 14.8
6.7 ± 10.4 7.3 ± 15.5
(p=n.s.) (p=n.s.)
Sensitivity/specificity for the detection of abnormal liver lesions MRI before Feridex I.V. vs. Final diagnosis:* Sensitivity 91% 92%
  Specificity 71% 77%
MRI after Feridex I.V. vs. Final diagnosis:*  
  Sensitivity 95% 92%
  Specificity 76% 85%
CECT vs. Final diagnosis:*  
  Sensitivity 96% 98%
  Specificity 67% 58%
* Final diagnosis: e.g., by biopsy, surgical resection, autopsy, MRI procedures other than with Feridex I.V. (ferumoxides injectable solution) , CECT, ultrasound, or other clinical information.
** MRI (magnetic resonance image), CECT (contrast enhanced computerized tomography)

In various types of liver lesions, Feridex I.V. (ferumoxides injectable solution) caused a smaller decrease in the signal intensity (59%–105% of the unenhanced) than in the surrounding liver (28%–41% of the unenhanced). The signal intensity changes are not characterized sufficiently to support distinguishing between types of lesions or diseases. Whether patients with cirrhosis have similar changes in signal intensity is not known.

PERCENT DECREASE IN MRI SIGNAL INTENSITY (SI) ON T2 IMAGES AFTER FERIDEX I.V. (ferumoxides injectable solution)

Disease State Surrounding Liver Lesions in Question
N % decrease in SI after Feridex I.V. N % decrease in SI after Feridex I.V.
Patients with benign, malignant, hepatocellular and non-hepatocellular lesions (excluding cirrhosis) 162 59–72% 153 0–41%

Imaging of the spleen by Feridex I.V. (ferumoxides injectable solution) has not been adequately studied.

Last reviewed on RxList: 12/2/2009
This monograph has been modified to include the generic and brand name in many instances.

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