Professional Information
Ferumoxides (Systemic)
VA CLASSIFICATION
Primary: DX900
Commonly used brand name(s): Feridex I.V.
Note: For a listing of dosage forms and brand names by country availability, see Dosage Forms section(s).
†Not commercially available in Canada.
Category:
Diagnostic aid, superparamagnetic (liver disorders)—
Note: Ferumoxides is a dextran-coated colloidal iron oxide {01} {11} {12} {13} {15}.
Indications
Accepted
Liver imaging, magnetic resonance—Ferumoxides is indicated to provide contrast enhancement of the T2-weighted images during magnetic resonance imaging (MRI), and thus facilitate detection and evaluation of lesions of the liver that are associated with an alteration in the reticuloendothelial system (RES) {01} {06} {07} {10} {11} {14} {15} {19} {20} {21} {22}.
Pharmacology/Pharmacokinetics
Physicochemical characteristics:
Source—
Obtained from a reaction of ferric chloride and ferrous chloride in the presence of ammonia and dextran T-10 {13}.
Chemical group—
A nonstoichiometric magnetite {01} {13}.
Osmolality
340 mOsmol per kg of water {01}.
Mechanism of action/Effect:
Contrast enhancement is based on the behavior of protons when placed in a strong magnetic field, which is interpreted and transformed into images by magnetic resonance (MR) instruments. Superparamagnetic agents have very large net magnetic susceptibilities (the ability to become magnetized in an external magnetic field) {12}. MR images are based on proton density and proton relaxation dynamics {12}. MR instruments can record two different relaxation processes, the T1 (spin-lattice or longitudinal relaxation time) and the T2 (spin-spin or transverse relaxation time) {12}. In magnetic resonance imaging (MRI), visualization of normal and pathological tissue depends in part on variations in the radiofrequency signal intensity that occur with changes in proton density, alteration of the T1, and variation in the T2 {02} {05} {12} {18}.
Ferumoxides predominantly affects T2 relaxation time. It functions as a negative contrast agent {12}. When placed in a magnetic field, ferumoxides shortens the relaxation time for nearby hydrogen atoms and reduces signal intensity in normal tissues {01} {04}. This results in signal loss (i.e., image darkening) on mid-T1/T2 or strongly T2-weighted images {01} {05} {06} {08} {12} {14}. The iron oxide–based particles in ferumoxides localize in normal liver and spleen parenchyma, causing a loss of signal on MR images {09} {12} {15}. Tissues with decreased reticuloendothelial system (RES) function (i.e., no phagocytic activity, such as occurs in metastases, primary hepatic carcinoma, cysts and various benign tumors, adenomas, and hyperplasia) retain their native signal intensity {01} {08} {14} {15}. Since MR signal intensity is decreased in normal liver and spleen, areas of metastatic disease are seen as areas of higher signal intensity; thus the contrast between normal and abnormal tissue is enhanced {09} {12} {20}.
Distribution:
Ferumoxides is rapidly removed from the blood by phagocytic cells of the reticuloendothelial system and dissociated into iron and dextran {13} {15}. The released iron follows the usual metabolic pathway, binding to protein moieties to form hemosiderin or ferritin or, to a lesser extent, transferrin {01} {15} {16}.
Biotransformation:
Iron enters the normal iron metabolism cycle, as demonstrated by transient increases in serum iron values 1 day after ferumoxides administration and increases in serum ferritin values 1 to 7 days after ferumoxides administration {01} {15}.
Half-life:
Elimination:
2.4 ± 0.2 hours {01}.
Peak serum concentration:
5.5 ± 0.6 micrograms per mL (mean) {01}.
Elimination:
Renal (less than 2% of dose excreted) {01}. No physiologic system of elimination exists for iron {17}. Ferumoxides is completely cleared from the blood by 25 hours after administration {01}.
Precautions to Consider
Cross-sensitivity and/or related problems
Patients sensitive to parenteral preparations of iron, dextran, iron dextran, iron polysaccharide, or radiographic contrast media may be sensitive to ferumoxides also {01} {22}.
Carcinogenicity
Long-term animal studies to evaluate the carcinogenic potential of ferumoxides have not been performed {01}. Tumors at the injection site have been reported in humans who previously received intramuscular injections of therapeutic iron dextran products {01} {22}.
Mutagenicity
Ferumoxides demonstrated no mutagenic effects in the Ames test, the CHO/HGPRT mutation assay, a chromosome aberration test in CHO cells, an unscheduled DNA synthesis assay, and an in vivo mouse micronucleus test {01} {15}.
Pregnancy/Reproduction
Pregnancy—
Adequate and well-controlled studies with ferumoxides have not been done in humans {01}. Although there is no evidence that the magnetic and electric fields associated with MRI have an effect on human development, in vitro studies and theoretical predictions raise concern regarding the risk of exposure of the developing embryo and fetus to MR. More studies are needed to establish the safety of MRI procedures in pregnant patients {03}.
Ferumoxides has been shown to be teratogenic in rabbits at all studied doses. The smallest dose studied was approximately six times the human clinical dose on a mg per m 2 of body surface area basis {01}.
FDA Pregnancy Category C {01}.
Breast-feeding
It is not known whether ferumoxides is distributed into breast milk {01}. However, temporary discontinuation of nursing should be considered following administration of ferumoxides {22}.
Pediatrics
No information is available on the relationship of age to the effects of ferumoxides in pediatric patients. Safety and efficacy have not been established {01}.
Geriatrics
No information is available on the relationship of age to the effects of ferumoxides in geriatric patients {01}. However, clinical trials were conducted that included patients up to 89 years of age and geriatrics-specific problems that would limit the usefulness of this agent in the elderly were not reported {01}.
Diagnostic interference
The following have been selected on the basis of their potential clinical significance (possible effect in parentheses where appropriate)—not necessarily inclusive (» = major clinical significance):
With results of this test
Due to medical problems or conditions
Cirrhosis{01}{15} (patients with cirrhosis have been reported to have a lesser decrease in liver signal intensity than patients with other known or suspected liver lesions {01})
With other diagnostic test results
Iron concentrations, serum{01}{07} (transient increases in serum iron of 15 to 100% of baseline may occur 18 to 24 hours after ferumoxides administration, and increases in ferritin levels have been observed 1 to 7 days after administration {01}; serum iron levels return to normal in most patients within 7 days {01}; caution is recommended in the interpretation of serum iron levels in blood samples drawn within 1 week of administration of ferumoxides {22})
Medical considerations/Contraindications
The medical considerations/contraindications included have been selected on the basis of their potential clinical significance (reasons given in parentheses where appropriate)— not necessarily inclusive (» = major clinical significance).
See also Diagnostic interference .
Risk-benefit should be considered when the following medical problems exist
» Allergies or asthma, history of or{01}
» Autoimmune disorders, underlying or{01}
» Sensitivity to dextran, ferumoxides, iron preparations, or to radiographic contrast media{01}{22} (increased risk of anaphylactic reaction in patients with a history of allergies or asthma, with a known sensitivity to ferumoxides or with a history of prior reactions to parenteral iron preparations or to radiographic contrast media, or in patients with underlying immune disorders, autoimmunity, or immunodeficiencies that predispose to specific or nonspecific mediator release {01})
Iron overload–associated disorders, such as:
Anemia, chronic hemolytic, with frequent blood transfusions{01}
Hemosiderosis{01} (although the iron load resulting from administration of ferumoxides is low compared with the total store of iron in the human body {15}, caution is recommended in patients with disorders associated with iron overload {01})
Side/Adverse Effects
The following side/adverse effects have been selected on the basis of their potential clinical significance (possible signs and symptoms in parentheses where appropriate)—not necessarily inclusive:
Those indicating need for medical attention
Incidence less frequent or rare
Anaphylactic or allergic reaction{01} (itching, watery eyes; skin rash or hives; swelling of face; thickening of tongue; wheezing, tightness in chest, or troubled breathing{01})—reported in 0.5% of patients in clinical trials
back, leg, or groin pain, severe{01}
hypotension{01} (unusual tiredness or weakness, severe)
Note: Severe back, leg, or groin pain may develop within 1 to 15 minutes (up to 45 minutes) after infusion of ferumoxides {01}. The incidence of back pain has been reported to be higher in patients with cirrhosis {01}.
Those indicating need for medical attention only if they continue or are bothersome
Incidence less frequent
Brown discoloration of skin{01} —may occur if there is extravasation
nausea{01}{22}
vasodilation{01} (unusual warmth and flushing of skin)
Overdose
Overdose with ferumoxides has not been reported {01}.
Patient Consultation
As an aid to patient consultation, refer to Advice for the Patient, Magnetic Resonance Imaging Contrast Agents, Iron-containing (Diagnostic) .
In providing consultation, consider emphasizing the following selected information (» = major clinical significance):
Description of use
Action in the body: Accumulates in liver lesions, creating a local magnetic field; detection and evaluation of lesions possible with MR instruments
Before having this test
» Conditions affecting use, especially:
Sensitivity to ferumoxides, parenteral iron preparations, or radiographic contrast media
Pregnancy—Studies in rabbits show teratogenic effects
Breast-feeding—Temporary discontinuation of nursing may be necessary
Other medical problems, especially history of allergies or asthma or underlying autoimmune disorders
Preparation for this test
Special preparatory instructions may apply; patient should inquire in advance
Side/adverse effects
Signs of potential side effects, especially anaphylactic or allergic reactions, severe back, leg, or groin pain, or hypotension
General Dosing Information
The manufacturer's package insert or other appropriate literature should be consulted for specific techniques and procedures for the administration of ferumoxides.
Sensitivity test doses usually are not recommended since severe or fatal reactions to contrast media are not predictable from skin tests {01}. On some occasions severe or fatal reactions have occurred with a test dose of contrast media {22}. In most cases, a thorough medical history with attention to allergic, autoimmune, and immunodeficiency disorders may have greater predictive value {01}.
The amount of iron contained in a single dose of ferumoxides is 39 mg for a 70-kg individual {01}. The iron load resulting from the administration of ferumoxides is low compared with the total store of iron in the human body (approximately 3.5 grams) {15}.
Care must be taken during administration of any contrast media to avoid extravasation, especially in patients with severe arterial or venous disease {01} {22}.
During and for at least 60 to 120 minutes after injection of ferumoxides, the patient should be observed for possible severe reactions {01}. Competent healthcare personnel and emergency facilities should be available during this period {01}.
Imaging procedures may begin immediately after administration of ferumoxides, and should be completed within 3.5 hours after the end of the infusion {01}. In human clinical studies there was no difference in loss of MR signal intensity on images obtained in the first 3.5 hours after the infusion {01}.
Repeat imaging may be performed up to 3.5 hours after the original infusion without the need for reinjection {01}. At present there are no data regarding timing and safety of repeated injections of ferumoxides {01}.
In women, there is a higher pre-contrast signal intensity due to lower iron baseline levels, and therefore, a larger decrease in liver signal intensity in images {01}.
For treatment of adverse effects
Severe back, leg, or groin pain that may develop after infusion of ferumoxides may require treatment with corticosteroids, intravenous fluids, or skeletal muscle relaxants {01}.
Parenteral Dosage Forms
FERUMOXIDES INJECTION
Usual adult and adolescent dose
Liver imaging, magnetic resonance
Intravenous infusion, 0.56 mg of iron per kilogram of body weight, administered over a period of 30 minutes {01}.
Note: Dose must be diluted in 100 mL of 5% dextrose solution and administered through a 5-micron filter at a rate of 2 to 4 mL per minute {01}.
Usual pediatric dose
Liver imaging, magnetic resonance
Safety and efficacy have not been established {01}.
Usual geriatric dose
Liver imaging, magnetic resonance
See Usual adult and adolescent dose .
Strength(s) usually available
U.S.—
11.2 mg of iron per mL{01} (Rx) [Feridex I.V. (dextran 5.6 to 9.1 mg per mL) (citrate 0.25 to 0.53 mg per mL)]
Canada—
Not commercially available.
Packaging and storage:
Store between 2 and 30 °C (35 and 86 °F), unless otherwise specified by manufacturer {01}. Protect from freezing {01}.
Stability:
Ferumoxides injection is stable for 24 hours after dilution {01}.
Developed: 01/16/1997
Revised: 10/21/1997
References
- Feridex package insert (Advanced Magnetics—US), Rev 1996; Rec 12/96.
- Wolf GL. Magnetic resonance imaging and the future of cardiac imaging. Am J Cardiol 1989; 64: 60E-63E.
- National Institutes of Health panel issues report. Consensus development conference: Magnetic resonance imaging 1987; 6(14).
- Bulte JM, Vymazal J, Brooks RA, et al. Frequency dependence of MR relaxation times. II. Iron oxides. J Magn Reson Imaging 1993; 3(4): 641-8.
- Hendrick RE, Haacke EM. Basic physics of MR contrast agents and maximization of image contrast. J Magn Reson Imaging 1993; 3(1): 137-48.
- Winter TC III, Freeny PC, Nghiem HV, et al. MR imaging with IV superparamagnetic iron oxide: efficacy in the detection of focal hepatic lesion. Am J Roentgenol 1993; 161(6): 1191-8.
- Bellin MF, Zaim S, Auberton E, et al. Liver metastases: safety and efficacy of detection with superparamagnetic iron oxide in MR imaging. Radiology Dec 1994; 193(3): 593-5.
- Grangier C, Tourniaire J, Mentha G, et al. Enhancement of liver hemangiomas on T1-weighted MR SE images by superparamagnetic iron oxide particles. J Comput Assist Tomogr 1994; 18(6): 888-96.
- Hamm B, Staks T, Taupitz M, et al. Contrast-enhanced MR imaging of liver and spleen: first experience in humans with a new superparamagnetic iron oxide. J Magn Reson Imaging 1994; 4(5): 659-68.
- Hagspiel KD, Neidl KF, Eichenberger AC, et al. Detection of liver metastases: comparison of superparamagnetic iron oxide-enhanced and unenhanced MR imaging at 1.5 T with dynamic CT, intraoperative US, and percutaneous US. Radiology 1995; 196(2): 471-8.
- Ros PR, Freeny PC, Harms SE, et al. Hepatic MR imaging with ferumoxides: a multicenter clinical trial of the safety and efficacy in the detection of focal hepatic lesions. Radiology 1995; 196(2): 481-8.
- Nelson KL, Runge VM. Basic principles of MR contrast. Top Magn Reson Imaging 1995; 7(3): 124-36.
- Jung CW. Surface properties of superparamagnetic iron oxide MR contrast agents: ferumoxides, ferumoxtran, ferumoxsil. Magn Reson Imaging 1995; 13(5): 675-91.
- Schwartz LH, Seltzer SE, Tempany CM, et al. Superparamagnetic iron oxide hepatic MR imaging: efficacy and safety using conventional and fast spin-echo pulse sequences. J Magn Reson Imaging 1995; 5(5): 566-70.
- Petersein J, Saini S, Weissleder R. Liver II: iron oxide–based reticuloendothelial contrast agents for MR imaging. Clinical review. Magn Reson Imaging Clin N Am 1996; 4(1): 53-60.
- Pollitt E, Leibel R. Iron deficiency and behavior. J Pediatr 1976: 88: 372.
- McEvoy GK, editor. AHFS Drug information 90. Bethesda, MD: American Society of Hospital Pharmacists; 1990. p. 714-8.
- Mettler FA Jr, Muroff LR, Kulkarmi MV, editors. Magnetic resonance imaging and spectroscopy. New York: Churchill Livingstone, 1986: 231-5.
- Stark DD, Weissleder R, Elizordo G, et al. Superparamagnetic iron oxide: clinical application as a contrast agent for MR imaging of the liver. Radiology 1988; 168: 247-302.
- Saini S, Stark DD, Hahn PF, et al. Ferrite particles: a superparamagnetic MR contrast agent for enhanced detection of liver carcinoma. Radiology 1987 Jan; 162(Pt 1): 217-22.
- Saini S, Stark DD, Hahn PF, et al. Ferrite particles: a superparamagnetic MR contrast agent for the reticuloendothelial system. Radiology 1987 Jan; 162(Pt 1): 211-6.
- Reviewer's comments per monograph revision of 4/97.
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