산화철

In rats, the simultaneous administration of heparin was found to prolong the half-life of Feridex i.v. in the blood. The effects of Feridex i.v. administration on heparin anticoagulation are not known.

Potential pharmacokinetic interaction /with oral iron preparations/ (reduced absorption of concomitantly administered oral iron).

IDENTIFICATION AND USE: Ferumoxytol (Feraheme) is a superparamagnetic iron oxide nanoparticle with a polyglucose sorbitol carboxymethylether coating. It is a black to reddish brown aqueous colloidal product formulated into a solution for IV injection. Ferumoxytol is used for the treatment of iron deficiency anemia in adult patients with chronic kidney disease (CKD). Ferumoxytol is also used as a contrast agent. HUMAN EXPOSURE AND TOXICITY: Limited data are available regarding overdosage of Feraheme in humans. Excessive dosages of Feraheme may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. The following serious adverse reactions have been reported from the post-marketing experience with Feraheme: fatal, life-threatening, and serious anaphylactic-type reactions, cardiac/cardiorespiratory arrest, clinically significant hypotension, syncope, unresponsiveness, loss of consciousness, tachycardia/rhythm abnormalities, angioedema, ischemic myocardial events, congestive heart failure, pulse absent, and cyanosis. These adverse reactions have usually occurred within 30 minutes after the administration of Feraheme. Reactions have occurred following the first dose or subsequent doses of Feraheme. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Feraheme may have more severe outcomes. ANIMAL STUDIES: Administration of ferumoxytol during organogenesis, at doses of 31.6 mg Fe/kg/day in rats and 16.5 mg Fe/kg/day in rabbits, did not result in maternal or fetal effects. These doses are approximately 2 times the estimated human daily dose based on body surface area. In rats, administration of ferumoxytol during organogenesis at a maternally toxic dose of 100 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, caused a decrease in fetal weights. In rabbits, administration of ferumoxytol during organogenesis at a maternally toxic dose of 45 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, was associated with external and/or soft tissue fetal malformations and decreased fetal weights. In standard genotoxicity tests, ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay.

/SIGNS AND SYMPTOMS/ Overdose with Feridex i.v. has not been reported. Acute toxicity is apt to be related to iron overload, acute back pain and allergic events. Chronic administration of therapeutic iron dextran in excess of the total amount of iron needed for iron stores may lead to hemosiderosis.

/CASE REPORTS/ To investigate the incremental value of dynamic gadolinium-enhancement performed immediately after ferumoxides-enhanced magnetic resonance (MR) imaging on the detection of hepatocellular carcinoma in patients with cirrhosis. /Investigators/ retrospectively reviewed MR scans of 62 cirrhotic patients over a two-year period. Sequences included ferumoxides-enhanced T2-weighted fast spin echo followed by dynamic gadolinium-enhanced T1-weighted spoiled gradient echo. Two readers independently documented the presence of hepatocellular carcinoma on a three-point confidence scale, without and with gadolinium-enhanced images. The presence or absence of hepatocellular carcinoma was established by histopathology (58 patients) or follow-up imaging (four patients) over a mean period of nine months. A total of 71 hepatocellular carcinomas were found in 42 patients. There was no statistically significant difference in sensitivity for the diagnosis of hepatocellular carcinoma without vs. with gadolinium-enhanced images (68% vs. 74% for reader 1 and 62% vs. 73% for reader 2, respectively, P > 1.3). However, both readers showed a lower mean confidence for tumor detection without vs. with gadolinium-enhanced images (2.3 vs. 2.7 for reader 1, 2.3 vs. 2.9 for reader 2, P < 0.01). the addition of dynamic gadolinium-enhancement to ferumoxides-enhanced MR imaging did not improve hepatocellular carcinoma detection...

/SURVEILLANCE/ The purpose of this study was to assess acute and delayed adverse reactions to ferumoxides. 473 consecutive patients who underwent ferumoxides-enhanced MRI were enrolled in this study. Following non-contrast-enhanced MRI, patients were interviewed about their allergic history, and after ferumoxides-enhanced MRI, they were asked to fill out a questionnaire sheet to record any symptoms within one week. 345 of 473 questionnaires (72.9%) were returned. Fifty-eight of 345 patients (16.8%) showed some adverse reactions considered to be related to ferumoxides: 25 (7.2%) during administration, 25 (7.2%) later on the day of ferumoxides administration, and 17 (4.9%) within one week. Thirty-three patients (9.6%) showed only delayed adverse reactions. Delayed adverse reactions were more frequent in women than in men (p<0.01), and in patients with any allergic history than in those without such history (p<0.05). Acute adverse reactions tended to be more frequent in patients who had some adverse events to any contrast medium than in those with no such history (p=0.069). By using the questionnaire, the incidence of adverse reactions to ferumoxides (16.8%) was higher than previously reported from Japanese clinical trials.

/OTHER TOXICITY INFORMATION/ The possibility of a reaction including serious, life-threatening, fatal, anaphylactoid or cardiovascular reactions should always be considered. Increased risk is associated with a known sensitivity to iron or dextran, history of previous reaction to a radiographic contrast agent, known allergies, other hypersensitivities, and underlying immune disorders, autoimmunity or immunodeficiencies that predispose to specific or non specific mediator release.

/SIGNS AND SYMPTOMS/ Limited data are available regarding overdosage of Feraheme in humans. Excessive dosages of Feraheme may lead to accumulation of iron in storage sites potentially leading to hemosiderosis. Do not administer Feraheme to patients with iron overload.

/SIGNS AND SYMPTOMS/ Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving Feraheme. Initial symptoms may include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest. Only administer Feraheme when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions. Observe for signs or symptoms of hypersensitivity reactions during and for at least 30 minutes following Feraheme infusion including monitoring of blood pressure and pulse during and after Feraheme administration. Hypersensitivity reactions have occurred in patients in whom a previous Feraheme dose was tolerated.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Ferumoxytol

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Feridex i.v. is teratogenic in rabbits at all studied doses. The smallest dose studied was approximately six times the clinical dose when normalized to body surface area.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Feridex i.v. did not impair the fertility of male or female rats at dosages that were up to approximately 5 times the clinical dose when normalized to body surface area.

/GENOTOXICITY/ Feridex i.v. was not genotoxic in a series of studies that included the Ames test, the CHO/HGPRT forward mutation assay, a chromosome aberration test in CHO cells, an unscheduled DNA synthesis assay, and a micronucleus assay in mice.

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Administration of ferumoxytol during organogenesis, at doses of 31.6 mg Fe/kg/day in rats and 16.5 mg Fe/kg/day in rabbits, did not result in maternal or fetal effects. These doses are approximately 2 times the estimated human daily dose based on body surface area. In rats, administration of ferumoxytol during organogenesis at a maternally toxic dose of 100 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, caused a decrease in fetal weights. In rabbits, administration of ferumoxytol during organogenesis at a maternally toxic dose of 45 mg Fe/kg/day, approximately 6 times the estimated human daily dose based on body surface area, was associated with external and/or soft tissue fetal malformations and decreased fetal weights.

/GENOTOXICITY/ In standard genotoxicity tests, ferumoxytol showed no evidence of mutagenic activity in an in vitro Ames test or clastogenic activity in either an in vitro chromosomal aberration assay or an in vivo micronucleus assay.

/ALTERNATIVE and IN VITRO TESTS/ The physicochemical properties of superparamagnetic iron oxide nanoparticles (SPIOs) enable their application in the diagnostics and therapy of central nervous system diseases. However, since crucial information regarding side effects of particle-cell interactions within the central nervous system is still lacking, we investigated the influence of novel very small iron oxide particles or the clinically approved ferucarbotran or ferumoxytol on the vitality and morphology of brain cells. We exposed primary cell cultures of microglia and hippocampal neurons, as well as neuron-glia cocultures to varying concentrations of SPIOs for 6 and/or 24 hours, respectively. Here, we show that SPIO accumulation by microglia and subsequent morphological alterations strongly depend on the respective nanoparticle type. Microglial viability was severely compromised by high SPIO concentrations, except in the case of ferumoxytol. While ferumoxytol did not cause immediate microglial death, it induced severe morphological alterations and increased degeneration of primary neurons. Additionally, primary neurons clearly degenerated after very small iron oxide particle and ferucarbotran exposure. In neuron-glia cocultures, SPIOs rather stimulated the outgrowth of neuronal processes in a concentration- and particle-dependent manner. We conclude that the influence of SPIOs on brain cells not only depends on the particle type but also on the physiological system they are applied to.

In the post-marketing experience, fatal and serious anaphylactic type reactions presenting with cardiac/ cardiorespiratory arrest, clinically significant hypotension, syncope, and unresponsiveness have been reported. Elderly patients with multiple or serious co-morbidities who experience hypersensitivity reactions and/or hypotension following administration of Feraheme may have more severe outcomes.

While data specific to ferumoxides were not located(SRC, 2012), the literature suggests that some pharmaceutically active compounds originating from human and veterinary therapy are not eliminated completely in municipal sewage treatment plants and are therefore discharged into receiving waters(1). Wastewater treatment processes often were not designed to remove them from the effluent(2). Selected organic waste compounds may be degrading to new and more persistent compounds that may be released instead of or in addition to the parent compound(2).

A study of (59)Fe complexed iron-dextran utilizing isotonic saline in a 4-hour in vitro dialysis run indicated that less than 0.5% of the injected radio labeled iron dextran traversed the dialysis membrane. Feridex i.v. contains iron associated with dextran. Whether Feridex i.v. is dialyzable is not known.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

◉ Summary of Use during Lactation

◉ Summary of Use during Lactation

The pharmacokinetic (PK) behavior of Feraheme has been studied in healthy subjects and in patients with stage 5D of chronic kidney disease, on hemodialysis. Feraheme showed dose-dependent, capacity-limited elimination from the plasma with a half-life of **approximately 15 hours*

... Elimination half-life was 2.4 +/- 0.2 hours and total clearance 28.5 +/- 1.6 mL/min.

The pharmacokinetic (PK) behavior of Feraheme has been examined in healthy subjects and in patients with CKD stage 5D on hemodialysis. Feraheme exhibited dose-dependent, capacity-limited elimination from plasma with a half life of approximately 15 hours in humans.

Ferumoxytol metabolism is not dependent on renal function. It is removed from the circulation by the reticuloendothelial system of the liver, spleen, and bone marrow. Iron, bound to transferrin, is then transported in the plasma and distributed to the bone marrow for the synthesis of hemoglobin, to the reticuloendothelial system for storage, and to all cells for enzymes containing iron, and to placental cells if needed to meet fetal needs. Transferrin eventually becomes available for recycling. In normal adults, 90% of metabolized iron is conserved and reutilized repeatedly.

The iron in Feridex i.v. 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.

G6N3J05W84

FERUMOXIDES NON-STOICHIOMETRIC MAGNETITE

Mechanisms of Action [MoA] - Magnetic Resonance Contrast Activity

Established Pharmacologic Class [EPC] - Paramagnetic Contrast Agent

Ferumoxides non-stoichiometric magnetite is a Paramagnetic Contrast Agent. The mechanism of action of ferumoxides non-stoichiometric magnetite is as a Magnetic Resonance Contrast Activity.

CLH5FT6412

Agents which improve the quality of the blood, increasing the hemoglobin level and the number of erythrocytes. They are used in the treatment of anemias.

Specialized solutions for PARENTERAL NUTRITION. They may contain a variety of MICRONUTRIENTS; VITAMINS; AMINO ACIDS; CARBOHYDRATES; LIPIDS; and SALTS.

Bioavailability studies were not conducted as ferumoxytol has been developed for IV administration only. Iron therapy dosage is individualized according to specific goals for blood iron concentrations, iron storage parameters (e.g., ferritin, transferrin saturation), and serum hemoglobin concentrations. Iron toxicity is possible with excessive or unnecessary iron therapy. Systemic iron is stored in ferritin and hemosiderin, which are utilized for future production of hemoglobin. The absorption of iron depends on the route of administration. The tissue that first clears parenterally ingested iron from the plasma determines its bioavailability. If the reticuloendothelial system clears iron effectively, only small amounts will become available over time to the bone marrow. Transferrin accepts iron from the intestinal tract and also from sites of hemoglobin storage and destruction.

Iron can either become a component of intracellular ferritin or be transferred to erythroid precursor cells.

The population mean estimates for volume of distribution of the central compartment (V(1)), maximum elimination rate (V(max)), and ferumoxytol concentration at which rate of metabolism would be one-half of V(max) (K(m)) were 2.71 l, 14.3 mg/hr, and 77.5 mg/L, respectively.

Since there is no renal clearance, ferumoxytol is safe in renal failure patients. One study estimated the clearance to be **0.0221 L/h**.

Three healthy, adult male volunteers received a dose of Feridex I.V. 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 ug/mL and total clearance 28.5 +/- 1.6 mL/min.

Feridex i.v. 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.