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IRON DEXTRAN AND RELATED AGENTS

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) IRON DEXTRAN: Iron dextran is a complex of ferric hydroxide and dextran for intramuscular and intravenous use.
    B) FERUMOXYTOL: Ferumoxytol is a carbohydrate-coated iron oxide for intravenous use that releases iron in the macrophages of the liver, spleen, and bone marrow.
    C) FERRIC CARBOXYMALTOSE: Ferric carboxymaltose releases iron via a carbohydrate polymer that is complexed with colloidal iron (III) hydroxide.

Specific Substances

    A) IRON DEXTRAN
    1) A 100
    2) B 75
    3) Chinofer
    4) Dextran iron complex
    5) Dextrofer 75
    6) Eixendextran (German)
    7) Fe-Dextran
    8) Fenate
    9) Ferdex 100
    10) Ferric dextran
    11) Ferridextran
    12) Ferrodextran
    13) Ferroglucin
    14) Ferroglukin 75
    15) Imferon
    16) Imposil
    17) Iro-Jex
    18) Iron dextran
    19) Iron dextran injection
    20) Iron hydrogenated dextran
    21) Iron-dextran complex
    22) Ironorm injection
    23) Myofer 100
    24) Polyfer
    25) Prolongal
    26) Ursoferran
    FERUMOXYTOL
    1) CAS 1309-38-2
    FERRIC CARBOXYMALTOSE
    1) CAS 9007-72-1

    1.2.1) MOLECULAR FORMULA
    1) FERRIC CARBOXYMALTOSE: [FeOx(OH)y(H2O)z]n [((C6H10O5)m (C6H12O7))l]k; where n is approximately 10(3); m is approximately 8; l is approximately 11; k is approximately 4
    2) FERUMOXYTOL: Fe5874O8752-C11719H18682O9933Na414

Available Forms Sources

    A) FORMS
    1) IRON DEXTRAN
    a) Iron dextran is available as INFeD(R) (Iron Dextran Injection, USP) containing 50 mg/mL of elemental iron (as an iron dextran complex) in a 2 mL single dose vial for intravenous or intramuscular use, along with 0.9% sodium chloride for injection (Prod Info INFeD(R), 1996). It is available in cartons of 10 (Prod Info INFeD(R) intravenous, intramuscular injection, 2008).
    2) FERUMOXYTOL
    a) Ferumoxytol is available as Feraheme(TM) (Ferumoxytol Injection) containing 30 mg/mL of elemental iron in a 17 mL single dose vial for intravenous use. It is also available in cartons of 10 single dose vials (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    3) FERRIC CARBOXYMALTOSE
    a) Ferric carboxymaltose injection is available as 750 mg iron/15 mL single-use vials for intravenous use (Prod Info INJECTAFER(R) intravenous injection, 2013).
    B) USES
    1) IRON DEXTRAN
    a) Iron dextran is indicated in patients who are unable to tolerate oral iron supplementation for the treatment of iron deficiency anemia; in patients on chronic hemodialysis or with chronic gastrointestinal losses; or in surgical patients who refuse blood transfusions (Prod Info INFeD(R) intravenous, intramuscular injection, 2008; Burns & Pomposelli, 1999).
    b) Ongoing, small intravenous doses have been used in the treatment of anemia in patients with chronic renal failure to promote erythropoiesis and to prevent iron deficiency (JEF Reynolds , 2000).
    2) FERUMOXYTOL
    a) Ferumoxytol is indicated in patients for the treatment of iron deficiency anemia in adult patients with chronic renal impairment (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    3) FERRIC CARBOXYMALTOSE
    a) Ferric carboxymaltose is an intravenous iron replacement indicated to treat iron deficiency anemia in adults who cannot tolerate oral iron, who have had unsatisfactory responses to oral iron, or adults with non-dialysis dependent chronic kidney disease (Prod Info INJECTAFER(R) intravenous injection, 2013).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) USES: Iron dextran is indicated in patients who are unable to tolerate oral iron supplementation for the treatment of iron deficiency anemia. Ferumoxytol is indicated in patients for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. Ferric carboxymaltose is an intravenous iron replacement indicated to treat iron deficiency anemia in adults who cannot tolerate oral iron, who have had unsatisfactory responses to oral iron, or adults with non-dialysis dependent chronic kidney disease.
    B) PHARMACOLOGY: Ferric carboxymaltose releases iron via a carbohydrate polymer that is complexed with colloidal iron (III) hydroxide. Ferumoxytol, a carbohydrate-coated iron oxide releases iron within vesicles in the macrophages of the liver, spleen, and bone marrow where it then enters into either the intracellular storage iron pool, or is transferred to plasma transferrin and is incorporated into hemoglobin by erythroid precursor cells. Iron dextran is a complex of ferric oxyhydroxide and a polyglucose that restores hemoglobin and depleted iron through the action of its iron component that forms hemosiderin or ferritin and transferrin by binding to protein moieties.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) IRON DEXTRAN: Most adverse effects have been described as self-limited or mild following iron dextran therapy. Anaphylaxis and hypersensitivity reactions have occurred within the first several minutes of administration after test doses, as well as with therapeutic doses of iron dextran. A high incidence of moderate to high fever, chills, arthralgia, backache, dizziness, headache, malaise, myalgia, nausea, and vomiting have been reported 1 to 2 days following the intramuscular and intravenous administration of iron dextran. Other adverse effects included chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension, tachycardia, bradycardia, flushing, dysrhythmias, flushing, urticaria, pruritus, purpura, rash, cyanosis, abdominal pain, diarrhea, leukocytosis, lymphadenopathy, injection site pain, cellulitis, swelling, inflammation, seizures, syncope, weakness, unresponsiveness, paresthesia, disorientation, numbness, unconsciousness, respiratory arrest, dyspnea, bronchospasm, wheezing, and hematuria.
    2) FERRIC CARBOXYMALTOSE: The most common adverse effects included nausea, hypertension, flushing, hypophosphatemia, and dizziness. Other adverse effects include vomiting, injection site discoloration, headache, elevated liver enzymes, dysgeusia, hypotension, abdominal pain, diarrhea, urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, and syncope.
    3) FERUMOXYTOL: Most adverse effects have been described as self-limited or mild following ferumoxytol therapy. Anaphylaxis and hypersensitivity reactions have been reported. Common adverse effects include hypotension, chest pain, diarrhea, dizziness, urticaria, pruritus, purpura, angioedema, and rash.
    E) WITH POISONING/EXPOSURE
    1) There are limited reports of overdose, and acute symptoms are unlikely based on the route of administration. Very high doses of these agents can cause iron overload syndrome and exogenous hemosiderosis. A patient developed hypophosphatemic osteomalacia after receiving ferric carboxymaltose 4000 mg over 4 month. Following the discontinuation of ferric carboxymaltose, the patient recovered partially. Hemosiderosis with multiple joint disorder, walking disability and asthenia developed in a patient after receiving ferric carboxymaltose 18,000 mg over 6 months.
    0.2.20) REPRODUCTIVE
    A) Iron dextran, ferumoxytol, and ferric carboxymaltose are classified as FDA pregnancy category C. There are no adequate and well-controlled studies of ferric carboxymaltose in pregnant women. Administer ferric carboxymaltose during pregnancy only if the potential maternal benefit outweighs the potential fetal risk. In animal studies, fetal and maternal toxicity and teratogenic and embryocidal effects were observed in animals given iron dextran. Administer iron dextran during pregnancy only if potential maternal benefit outweighs potential fetal risk. Traces of unmetabolized iron dextran have been found in human breast milk. Exercise caution when administering ferric carboxymaltose or iron dextran to a nursing woman. It is not known if ferumoxytol is excreted into human milk; the manufacturer recommends either discontinuing nursing or avoiding ferumoxytol therapy.
    0.2.21) CARCINOGENICITY
    A) IRON DEXTRAN - There is a potential risk of carcinogenesis with the use of iron dextran.
    B) FERRIC CARBOXYMALTOSE AND FERUMOXYTOL - No carcinogenic testing has been completed.

Laboratory Monitoring

    A) Monitor serum electrolytes, CBC, serum iron levels, liver enzymes, renal function, PT/INR, and PTT in patients following a significant exposure.
    B) Peak serum iron levels can be delayed after administration. Elevated serum iron levels with no associated clinical evidence of toxicity have been reported after iron dextran overdose and may be present in the first 24 hours following ferumoxytol administration. Clinical signs and symptoms are more important than serum iron levels in assessing the need for treatment and chelation.
    C) IRON DEXTRAN may cause laboratory interference with serum bilirubin (falsely increased) and serum calcium (falsely decreased), as well as producing a brown color to the serum (5 mL or more).

Treatment Overview

    0.4.6) PARENTERAL EXPOSURE
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) Treatment is symptomatic and supportive. Manage mild hypotension with IV fluids. Unlike ferrous sulfate, the route of exposure may limit the risk of developing iron toxicity. Based on iron dextran's delayed absorption via the parenteral route, symptoms can be delayed as iron levels may not peak for 24 to 48 hours. Continue to obtain levels as indicated. Once absorbed via the parenteral route, iron dextran is expected to act similarly to other ferrous compounds. Refer to the IRON management for further information regarding treatment of toxicity.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Anaphylaxis has been commonly reported following therapy, and has occurred following test doses of iron dextran. In patients with acute allergic reaction, oxygen therapy, bronchodilators, diphenhydramine, corticosteroids, vasopressors and epinephrine may be required. Monitor blood pressure and respiratory function. Refer to the IRON management for further information regarding treatment of severe toxicity. Administer deferoxamine if signs/symptoms of iron poisoning develop (severe vomiting/diarrhea, acidosis, hypotension). Faster rates or IV boluses may cause hypotension in some individuals.
    C) DECONTAMINATION
    1) Gastrointestinal decontamination is not recommended; administered via the parenteral route.
    D) AIRWAY MANAGEMENT
    1) Ensure adequate ventilation and perform endotracheal intubation early in patients with severe allergic reactions.
    E) ANTIDOTE
    1) None.
    F) PATIENT DISPOSITION
    1) HOME CRITERIA: A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    2) OBSERVATION CRITERIA: Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.
    3) ADMISSION CRITERIA: Patients with severe symptoms despite treatment should be admitted.
    4) CONSULT CRITERIA: Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    G) PITFALLS
    1) When managing a suspected overdose, the possibility of multidrug involvement should be considered.
    H) PHARMACOKINETICS
    1) FERRIC CARBOXYMALTOSE: Tmax: 15 minutes to 1.21 hours. Vd: 3 L. Renal elimination is negligible. Ferric carboxymaltose is rapidly cleared from the plasma, the terminal half-life ranges from 7 to 12 hours. FERUMOXYTOL: The mean peak plasma concentration following administration of ferumoxytol is 206 mcg/mL; peak plasma concentrations typically occur approximately 0.32 hours after administration. Vd: Following two 510 mg doses of ferumoxytol administered within 24 hours, Vd was 3.16 L. Elimination half-life: Approximately 15 hours. IRON DEXTRAN: IM iron dextran is absorbed from the parenteral site into the capillaries and the lymphatic system within 72 hours of a prescribed dose. The remaining portion of the dose is absorbed over 3 to 4 weeks. Protein binding: Iron is immediately bound to available protein moieties to form hemosiderin or ferritin. Excretion: Only small amounts of IM iron are lost via the urinary pathway following administration of iron dextran. Elimination half-life: From 5 hours (determined by using a method to measure iron dextran separately from the transferrin-bound iron) up to more than 20 hours (obtained by measuring total iron, both circulating and bound).
    I) DIFFERENTIAL DIAGNOSIS
    1) Includes other agents that cause hypotension (eg, vasodilators, beta blockers, calcium channel blockers), hepatotoxicity (eg, acetaminophen, ethanol), or anaphylaxis.

Range Of Toxicity

    A) TOXICITY: IRON DEXTRAN: An overdosage of iron dextran is unlikely to produce acute symptoms of iron toxicity. Adverse effects can be delayed up to 1 to 2 days, but have been reported following a single dose during therapeutic use. Doses of more than 500 mg have been associated with an increased risk of developing severe anaphylactoid reactions. A dose of 32 mL resulted in moderate toxicity in an adult; a child developed no symptoms following an intravenous dose of 1300 mg over a 48-hour period. FERRIC CARBOXYMALTOSE: A patient developed hypophosphatemic osteomalacia after receiving ferric carboxymaltose 4000 mg over 4 month. Following the discontinuation of ferric carboxymaltose, the patient recovered partially. Hemosiderosis with multiple joint disorder, walking disability and asthenia developed in a patient after receiving ferric carboxymaltose 18,000 mg over 6 months.
    B) THERAPEUTIC DOSES: Iron replacement is based on several indicators. The maximum daily dose is 2 mL of undiluted iron dextran.

Clinical Effects

Summary Of Exposure

    A) USES: Iron dextran is indicated in patients who are unable to tolerate oral iron supplementation for the treatment of iron deficiency anemia. Ferumoxytol is indicated in patients for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. Ferric carboxymaltose is an intravenous iron replacement indicated to treat iron deficiency anemia in adults who cannot tolerate oral iron, who have had unsatisfactory responses to oral iron, or adults with non-dialysis dependent chronic kidney disease.
    B) PHARMACOLOGY: Ferric carboxymaltose releases iron via a carbohydrate polymer that is complexed with colloidal iron (III) hydroxide. Ferumoxytol, a carbohydrate-coated iron oxide releases iron within vesicles in the macrophages of the liver, spleen, and bone marrow where it then enters into either the intracellular storage iron pool, or is transferred to plasma transferrin and is incorporated into hemoglobin by erythroid precursor cells. Iron dextran is a complex of ferric oxyhydroxide and a polyglucose that restores hemoglobin and depleted iron through the action of its iron component that forms hemosiderin or ferritin and transferrin by binding to protein moieties.
    C) EPIDEMIOLOGY: Overdose is rare.
    D) WITH THERAPEUTIC USE
    1) IRON DEXTRAN: Most adverse effects have been described as self-limited or mild following iron dextran therapy. Anaphylaxis and hypersensitivity reactions have occurred within the first several minutes of administration after test doses, as well as with therapeutic doses of iron dextran. A high incidence of moderate to high fever, chills, arthralgia, backache, dizziness, headache, malaise, myalgia, nausea, and vomiting have been reported 1 to 2 days following the intramuscular and intravenous administration of iron dextran. Other adverse effects included chest pain, chest tightness, shock, cardiac arrest, hypotension, hypertension, tachycardia, bradycardia, flushing, dysrhythmias, flushing, urticaria, pruritus, purpura, rash, cyanosis, abdominal pain, diarrhea, leukocytosis, lymphadenopathy, injection site pain, cellulitis, swelling, inflammation, seizures, syncope, weakness, unresponsiveness, paresthesia, disorientation, numbness, unconsciousness, respiratory arrest, dyspnea, bronchospasm, wheezing, and hematuria.
    2) FERRIC CARBOXYMALTOSE: The most common adverse effects included nausea, hypertension, flushing, hypophosphatemia, and dizziness. Other adverse effects include vomiting, injection site discoloration, headache, elevated liver enzymes, dysgeusia, hypotension, abdominal pain, diarrhea, urticaria, dyspnea, pruritus, tachycardia, erythema, pyrexia, chest discomfort, chills, angioedema, back pain, and syncope.
    3) FERUMOXYTOL: Most adverse effects have been described as self-limited or mild following ferumoxytol therapy. Anaphylaxis and hypersensitivity reactions have been reported. Common adverse effects include hypotension, chest pain, diarrhea, dizziness, urticaria, pruritus, purpura, angioedema, and rash.
    E) WITH POISONING/EXPOSURE
    1) There are limited reports of overdose, and acute symptoms are unlikely based on the route of administration. Very high doses of these agents can cause iron overload syndrome and exogenous hemosiderosis. A patient developed hypophosphatemic osteomalacia after receiving ferric carboxymaltose 4000 mg over 4 month. Following the discontinuation of ferric carboxymaltose, the patient recovered partially. Hemosiderosis with multiple joint disorder, walking disability and asthenia developed in a patient after receiving ferric carboxymaltose 18,000 mg over 6 months.

Vital Signs

    3.3.3) TEMPERATURE
    A) WITH THERAPEUTIC USE
    1) Fever has been reported with therapy and may be related to a hypersensitivity response (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Prod Info FERAHEME(TM) injection, intravenous, 2009).
    2) INCIDENCE (IRON DEXTRAN): Bielory (1990) reported that 30% of individuals may develop a hypersensitivity response within the first 24 to 48 hours following iron dextran which includes fever and arthralgia (Bielory, 1990).
    3) INCIDENCE (FERUMOXYTOL): In clinical trials of patients receiving two injections of 510 mg ferumoxytol (n=605), fever was reported in 1% of patients (Prod Info FERAHEME(TM) injection, intravenous, 2009).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) Hypotension has been reported following intravenous injections and may occur along with flushing as a result of too rapid an infusion (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Prod Info FERAHEME(TM) injection, intravenous, 2009).
    b) IRON DEXTRAN: In a case-control study of patients on chronic dialysis who experienced adverse effects (n=165) to intravenous iron dextran, hypotension (23%) was reported as one of the major adverse events (Fletes et al, 2001).
    c) FERUMOXYTOL: In clinical trials of patients receiving two injections of 510 mg ferumoxytol (n=605), hypotension was reported in 2.5% of patients (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    d) FERRIC CARBOXYMALTOSE: In clinical trials, hypotension occurred in 1% of patients treated with ferric carboxymaltose 15 mg/kg IV (maximum single dose, 750 mg iron; maximum cumulative dose, 1500 mg iron) (n=1775) compared with 1.9% of patients treated with oral iron, other forms of IV iron, or both (n=1783) and 0% of patients treated with oral iron (n=253) (Prod Info INJECTAFER(R) intravenous injection, 2013).
    B) CARDIOVASCULAR FINDING
    1) WITH THERAPEUTIC USE
    a) IRON DEXTRAN: Chest pain, cardiac arrest, hypertension, tachycardia, bradycardia and dysrhythmias have been described with iron dextran therapy; the incidence of these events are not known (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Fletes et al, 2001).
    b) CASE SERIES - IRON DEXTRAN
    1) In a review of 573 patients on dialysis who were treated with iron dextran, one patient developed cardiac arrest (Burns & Pomposelli, 1999).
    2) INCIDENCE: In a case-control study of patients on chronic dialysis who experienced adverse effects (n=165) to intravenous iron dextran, chest pain (19%), dysrhythmias (3%), and asystole (1%) were reported as major adverse cardiovascular effects (Fletes et al, 2001).
    c) FERUMOXYTOL: In clinical trials of patients receiving two injections of 510 mg ferumoxytol (n=605), chest pain was reported in 1.3% of patients (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    d) FERRIC CARBOXYMALTOSE: Syncope has been reported in postmarketing surveillance with ferric carboxymaltose IV use (Prod Info INJECTAFER(R) intravenous injection, 2013).
    C) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) FERUMOXYTOL (CASE REPORT): A 71-year-old man, with a medical history of diabetes, hypertension, stroke, iron deficiency anemia, and chronic kidney disease, became unresponsive and developed cardiac arrest within 30 minutes of receiving a ferumoxytol (510 mg) infusion. His vital signs included a blood pressure of 100/60 mmHg, heart rate of 65 beats/min, respiratory rate of 8 breaths/min, and oxygen saturation of 85%. He was successfully resuscitated and intubated, and received vasopressor infusions for hypotension. He did not develop any angioedema, urticaria, or wheezing. Laboratory results revealed a serum creatinine of 3 mg/dL, BUN 45 mg/dL, potassium 4.6 mEq/L, lactate 5.1 mmol/L, INR 1.2, and troponin 4.26 ng/mL. Severe hypoxic brain injuries, including multiple ischemic infarcts and areas of necrosis, were observed on a head CT and MRI imaging. His condition did not improve despite supportive care and he died 8 days after presentation (Almulhim et al, 2015).
    D) HYPERTENSIVE EPISODE
    1) WITH THERAPEUTIC USE
    a) FERRIC CARBOXYMALTOSE: In clinical trials, transient increases in systolic blood pressure occurred in 6% of patients (106 of 1775) treated with ferric carboxymaltose 15 mg/kg IV (maximum single dose, 750 mg iron; maximum cumulative dose, 1500 mg iron). Facial flushing, dizziness, or nausea sometimes accompanied these elevations, which generally occurred immediately after dosing and were self-limiting within 30 minutes. Monitor patients for signs and symptoms of hypotension after each administration (Prod Info INJECTAFER(R) intravenous injection, 2013).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DISORDER OF RESPIRATORY SYSTEM
    1) WITH THERAPEUTIC USE
    a) Dyspnea, bronchospasm, wheezing, cyanosis, and respiratory arrest have been observed and are probably related to an anaphylactoid response (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Burns & Pomposelli, 1999).
    b) INCIDENCE (IRON DEXTRAN): In a case-control study of patients on chronic dialysis who experienced adverse effects (n=165) to intravenous iron dextran infusion, dyspnea (43%) was the most common major adverse event. Apnea (2%) was reported infrequently (Fletes et al, 2001).
    c) INCIDENCE (FERUMOXYTOL): In clinical trials of patients receiving two injections of 510 mg ferumoxytol (n=605), cough and dyspnea were reported in 1.3% and 1% of patients, respectively (Prod Info FERAHEME(TM) injection, intravenous, 2009).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) CENTRAL NERVOUS SYSTEM FINDING
    1) WITH THERAPEUTIC USE
    a) IRON DEXTRAN: The following have been reported with the use of iron dextran: seizures, syncope, headache, weakness, unresponsiveness, paresthesia, dizziness, disorientation, numbness and unconsciousness (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014). No data were available to determine the incidence of these adverse effects.
    b) IRON DEXTRAN: A cluster of symptoms that occurs with moderate frequency, 1 to 2 days after exposure, have included the following: dizziness, headache, moderate to high fever, chills, backache, malaise, nausea, vomiting, myalgia, and arthralgia with either intramuscular or intravenous administration (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014).
    c) CASE SERIES - IRON DEXTRAN
    1) Barton et al (2000) treated 135 patients with iron dextran and reported 3 cases of weakness and dizziness, and 1 case of paresthesia (Barton et al, 2000).
    2) INCIDENCE: In a case-control study of patients on chronic dialysis who experienced adverse effects (n=165) to intravenous iron dextran infusion, loss of consciousness (12%) and altered mental status (6%) were reported as major adverse neurological effects. Other minor effects included: tremors (6%), dizziness (5%), restlessness (3%), and fatigue (2%) (Fletes et al, 2001).
    d) FERUMOXYTOL: In clinical trials of patients receiving two injections of 510 mg ferumoxytol (n=605), dizziness and headache were reported in 2.6% and 1.8% of patients, respectively (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    e) FERRIC CARBOXYMALTOSE: In clinical trials, paresthesia, dizziness, and headache were reported in patients receiving ferric carboxymaltose (Prod Info INJECTAFER(R) intravenous injection, 2013).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) DRUG-INDUCED GASTROINTESTINAL DISTURBANCE
    1) WITH THERAPEUTIC USE
    a) Abdominal pain, nausea, vomiting, diarrhea and metallic taste have been described following the therapeutic use of iron dextran, ferric carboxymaltose, and ferumoxytol (Prod Info INJECTAFER(R) intravenous injection, 2013; Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Prod Info FERAHEME(TM) injection, intravenous, 2009; Barton et al, 2000). Constipation and dysgeusia have also been reported in patients receiving ferric carboxymaltose (Prod Info INJECTAFER(R) intravenous injection, 2013).
    b) IRON DEXTRAN: In a case-control study of patients (n=165) on chronic dialysis receiving intravenous iron dextran, nausea (34%), abdominal pain (13%), and diarrhea (6%) were commonly reported adverse gastrointestinal effects (Fletes et al, 2001).
    c) FERUMOXYTOL: In clinical trials of patients receiving two injections of 510 mg ferumoxytol (n=605), nausea, abdominal pain and vomiting were reported in 3.1%, 1.3% and 1.5% of patients, respectively (Prod Info FERAHEME(TM) injection, intravenous, 2009).

Hepatic

    3.9.2) CLINICAL EFFECTS
    A) ABNORMAL LIVER FUNCTION
    1) WITH THERAPEUTIC USE
    a) A long-term complication of chronic excess iron (overload) is that the iron is sequestered by the reticuloendothelial system, which may result in hepatosplenic siderosis (Burns & Pomposelli, 1999). It has been observed, that elevated serum ferritin levels correlated with advanced hepatosplenic siderosis.
    B) LACK OF EFFECT
    1) WITH THERAPEUTIC USE
    a) IRON DEXTRAN: In a small study (n=20) of patients, with end-stage renal disease on home peritoneal dialysis with iron deficiency anemia, liver function tests remained unchanged following the administration of iron dextran (median dose 1000 mg {range, 325 to 1500 mg}) (Sloand et al, 1998). The limitations of study included its short duration and small sample size.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) LEUKOCYTOSIS
    1) WITH THERAPEUTIC USE
    a) IRON DEXTRAN: Leukocytosis and lymphadenopathy have developed during therapeutic use of iron dextran (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014). Lymphadenopathy may occur 1 to 3 days after administration as a result of deposition of iron dextran into the tissues (Burns & Pomposelli, 1999).
    B) THROMBOCYTOPENIC DISORDER
    1) WITH THERAPEUTIC USE
    a) CASE REPORT (IRON DEXTRAN): A 30-year-old with a history of iron deficiency anemia secondary to malabsorption was given iron dextran (100 mg/day, IM) for 8 days and developed asymptomatic thrombocytopenia (platelet count nadir of 20 x 10(9)/L). Therapy was discontinued and the patient was started on oral therapy, and the platelet count improved within two days. The authors suggested that this may have been an idiosyncratic response or the result of iron repletion causing thrombocytopenia.
    1) Animal studies have shown that erythropoietin stimulation of megakaryopoiesis is regulated by the adequacy of the iron supply. Studies suggest that erythroid and platelets precursors appear to share the same stem cell. When iron supply is inadequate, intense erythropoietin stimulation causes thrombocytosis, and when iron is available erythropoiesis predominates and megakaryopoiesis may become limited, temporarily (Go et al, 2000).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN FINDING
    1) WITH THERAPEUTIC USE
    a) Urticaria, pruritus, purpura, angioedema, and rash have been described following treatment with iron dextran and ferumoxytol (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Bailie et al, 2005; Prod Info FERAHEME(TM) injection, intravenous, 2009). Brown skin or tissue discoloration has been reported following intramuscular use of iron dextran (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014). Rash, mild pruritus, flushing/hot flush, angioedema, and injection site discoloration/pain have also been reported in patients receiving ferric carboxymaltose (Prod Info INJECTAFER(R) intravenous injection, 2013).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) ARTHRITIS
    1) WITH THERAPEUTIC USE
    a) IRON DEXTRAN: Arthritis symptoms, described as a reactivation in some patients with rheumatoid arthritis or collagen vascular disease, have been observed after therapy with iron dextran (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Burns & Pomposelli, 1999). It is suggested that individuals with autoimmune disease are at greater risk for anaphylaxis (Burns & Pomposelli, 1999).
    B) JOINT PAIN
    1) WITH THERAPEUTIC USE
    a) IRON DEXTRAN: Arthralgia, along with myalgia and bone aches, has been commonly reported during therapeutic use (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Barton et al, 2000; Fletes et al, 2001).
    b) INCIDENCE (IRON DEXTRAN): Bielory (1990) reported that 30% of individuals may develop a hypersensitivity response within the first 24 to 48 hours following iron dextran which includes symptoms of fever and arthralgia. Other symptoms that may develop as a result of iron deposition into the tissue is myalgia, phlebitis, and lymphadenopathy (Burns & Pomposelli, 1999).
    1) In a case-control study of patients on chronic dialysis who experienced adverse effects (n=165) to intravenous iron dextran, myalgia (3%) was infrequently reported (Fletes et al, 2001).
    c) INCIDENCE (FERUMOXYTOL): In clinical trials of patients receiving two injections of 510 mg ferumoxytol (n=605), back pain and muscle spasms were both reported in 1% of patients (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    C) RHABDOMYOLYSIS
    1) WITH THERAPEUTIC USE
    a) IRON DEXTRAN: Rhabdomyolysis has been reported in an adult with chronic malabsorption, selective IgA deficiency, and severe iron-deficiency anemia following intramuscular injection of iron dextran. Due to underlying nutritional and vitamin deficiencies the patient may have been at increased risk for free radical oxidative injury resulting in muscle damage (Burns & Pomposelli, 1999).

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) ANAPHYLACTOID REACTION
    1) WITH THERAPEUTIC USE
    a) INCIDENCE (IRON DEXTRAN): In some individuals, test doses have resulted in symptoms (characterized by a sudden onset of severe respiratory difficulty and/or cardiovascular collapse) (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014). Fatalities have been reported in some cases. Hypersensitivity reactions (including anaphylactoid responses) may occur in as few as 0.2% to almost 50% of individuals receiving iron dextran (Bielory, 1990).
    1) In a review by Burns & Pomposelli (1999), 3% of patients were described as having severe symptoms while 0.1 to 0.6% of patients developed life-threatening anaphylaxis following iron dextran therapy. Most cases occurred immediately after administration.
    2) In a case-control study of patients on chronic dialysis who experienced adverse effects to intravenous iron dextran, the majority of events (113 of 163 {69%}) occurred with the first dose (ie, either as a maintenance dose or the first of a planned course of injections) (Fletes et al, 2001).
    b) FERUMOXYTOL: Ferumoxytol may cause anaphylaxis and hypersensitivity reactions. In clinical studies, serious hypersensitivity reactions were reported in 0.2% (3/1726) of patients(Prod Info FERAHEME(TM) injection, intravenous, 2009).
    c) RISK FACTORS: Individuals with a history of autoimmune disease may be at greater risk for developing anaphylaxis (Burns & Pomposelli, 1999).
    d) FERRIC CARBOXYMALTOSE: Serious and life-threatening hypersensitivity reactions, including anaphylactic-type episodes, have occurred with ferric carboxymaltose use. These reactions have occasionally been fatal (Prod Info INJECTAFER(R) intravenous injection, 2013).
    B) HYPERSENSITIVITY REACTION
    1) WITH THERAPEUTIC USE
    a) FERUMOXYTOL (CASE REPORT): A 71-year-old man, with a medical history of diabetes, hypertension, stroke, iron deficiency anemia, and chronic kidney disease, became unresponsive and developed cardiac arrest within 30 minutes of receiving a ferumoxytol (510 mg) infusion. His vital signs included a blood pressure of 100/60 mmHg, heart rate of 65 beats/min, respiratory rate of 8 breaths/min, and oxygen saturation of 85%. He was successfully resuscitated and intubated, and received vasopressor infusions for hypotension. He did not develop any angioedema, urticaria, or wheezing. Laboratory results revealed a serum creatinine of 3 mg/dL, BUN 45 mg/dL, potassium 4.6 mEq/L, lactate 5.1 mmol/L, INR 1.2, and troponin 4.26 ng/mL. Severe hypoxic brain injuries, including multiple ischemic infarcts and areas of necrosis, were observed on a head CT and MRI imaging. His condition did not improve despite supportive care and he died 8 days after presentation (Almulhim et al, 2015).
    C) TRANSFUSION REACTION DUE TO SERUM PROTEIN REACTION
    1) WITH THERAPEUTIC USE
    a) IRON DEXTRAN: Serum sickness described as an immune-complex-mediated hypersensitivity vasculitis has developed in some individuals following the use of iron dextran (Bielory, 1990).
    1) CASE REPORT: A 37-year-old woman with a history of severe menorrhagia developed arthralgia, bifrontal headaches, fever, chest pain, and a burning nonpruritic cutaneous eruptions 9 days after receiving undiluted iron-dextran therapy for several days via a slow intravenous infusion (Bielory, 1990). An elevated erythrocyte sedimentation rate of 59 mm/h (normal 0 to 20) was reported. Symptoms resolved within 24 hours of starting prednisone; the patient was discharged on a tapered dose of steroids.

Reproductive

    3.20.1) SUMMARY
    A) Iron dextran, ferumoxytol, and ferric carboxymaltose are classified as FDA pregnancy category C. There are no adequate and well-controlled studies of ferric carboxymaltose in pregnant women. Administer ferric carboxymaltose during pregnancy only if the potential maternal benefit outweighs the potential fetal risk. In animal studies, fetal and maternal toxicity and teratogenic and embryocidal effects were observed in animals given iron dextran. Administer iron dextran during pregnancy only if potential maternal benefit outweighs potential fetal risk. Traces of unmetabolized iron dextran have been found in human breast milk. Exercise caution when administering ferric carboxymaltose or iron dextran to a nursing woman. It is not known if ferumoxytol is excreted into human milk; the manufacturer recommends either discontinuing nursing or avoiding ferumoxytol therapy.
    3.20.2) TERATOGENICITY
    A) EMBRYO/FETAL RISK
    1) A suspicion of possible iron teratogenicity has been noted in a retrospective study involving 1369 pregnant women. The data from this study showed that the incidence of congenital abnormalities was higher in women who had taken supplemental iron during the first trimester of pregnancy compared to women who did not take iron during this period. However, the overall incidence of congenital abnormalities in women who had taken iron during their entire pregnancy was the same as in the control group (Nelson & Forfar, 1971). In a subsequent prospective study of 6376 women, the incidence of fetal malformations was lower in the women who had taken iron during pregnancy compared to those who did not use supplemental iron. In addition, the women in the iron-treated group delivered infants with higher birth weights and also had a lower incidence of preterm births (Kullander & Kallen, 1976).
    B) ANIMAL STUDIES
    1) FERRIC CARBOXYMALTOSE
    a) In animal studies, IV infusions resulted in fetal malformations at an iron dose 23% of human weekly dose of 750 mg and spontaneous abortions at an iron dose of 12% of the human weekly dose based on body surface area administered over 1 hour on gestation days 6 to 19. Pre-implantation loss occurred at the highest iron dose of 18 mg/kg/day and maternal toxicity occurred at all doses (4.5, 9, 13.5, and 18 mg/kg/day). There was no evidence of teratogenicity or adverse effects on fetal survival with IV infusions in rats at iron doses up to approximately 40% of the human weekly doses based on body surface area on gestation days 6 to 17 or doses up to approximately 23% of the human weekly doses in a pre- and post-natal development study (Prod Info INJECTAFER(R) intravenous injection, 2013).
    2) FERUMOXYTOL
    a) Decreased fetal weights were reported when pregnant rats were given daily ferumoxytol injections during organogenesis of approximately 2 times the recommended 510 mg human dose (on a mg/m(2) basis) for 12 days (approximately 13 times the human therapeutic course of 1.02 g on a mg/m(2) basis). Exterior or soft tissue fetal malformations and decreased fetal weights were reported in pregnant rabbits given daily ferumoxytol injections during organogenesis of approximately 2 times the recommended 510 mg human dose (on a mg/m(2) basis) for 14 days (approximately 15 times the human therapeutic course of 1.02 g on a mg/m(2) basis) (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    3) IRON DEXTRAN
    a) During animal studies, no consistent adverse fetal effects were observed with iron dextran doses of 50 mg/kg or less. However, fetal and maternal toxicity was reported with IV doses of 90 mg/kg over a 14-day period. Doses approximately 3 times the maximum human doses resulted in teratogenic and embryocidal effects (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014).
    3.20.3) EFFECTS IN PREGNANCY
    A) PREGNANCY CATEGORY
    1) Iron dextran, ferric carboxymaltose, and ferumoxytol are classifies as FDA pregnancy category C (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014; Prod Info INJECTAFER(R) intravenous injection, 2013; Prod Info FERAHEME(TM) injection, intravenous, 2009).
    2) FERRIC CARBOXYMALTOSE: There are no adequate and well-controlled studies of ferric carboxymaltose in pregnant women. Administer ferric carboxymaltose during pregnancy only if the potential maternal benefit outweighs the potential fetal risk (Prod Info INJECTAFER(R) intravenous injection, 2013).
    3) IRON DEXTRAN: There are no adequate and well-controlled studies of iron dextran use in pregnant women. Administer iron dextran during pregnancy only if potential maternal benefit outweighs potential fetal risk (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014).
    3.20.4) EFFECTS DURING BREAST-FEEDING
    A) BREAST MILK
    1) FERRIC CARBOXYMALTOSE
    a) Mean breast milk iron levels were higher in lactating women who received IV ferric carboxymaltose (n=11). compared with lactating women who received oral ferrous sulfate (n=14) in a study in women with postpartum iron deficiency anemia (Prod Info INJECTAFER(R) intravenous injection, 2013).
    b) Exercise caution when administering ferric carboxymaltose to a nursing woman (Prod Info INJECTAFER(R) intravenous injection, 2013); however, ferrous salts were considered compatible with breastfeeding by the World Health Organization (Anon, 2002).
    2) FERUMOXYTOL
    a) It is not known if ferumoxytol is excreted into human milk; the manufacturer recommends either discontinuing nursing or avoiding ferumoxytol therapy (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    3) IRON DEXTRAN
    a) Traces of unmetabolized iron dextran have been found in human breast milk (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014). With supplementation, iron excreted in the breast milk is approximately 0.25 mg/day during normal lactation.(Harju, 1989).
    b) Exercise caution when administering to a lactating woman (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014). however, ferrous salts were considered compatible with breastfeeding by the World Health Organization (Anon, 2002).
    3.20.5) FERTILITY
    A) ANIMAL STUDIES
    1) FERRIC CARBOXYMALTOSE: No effects on mating function, fertility, or early embryonic development were reported during animal reproduction studies (Prod Info INJECTAFER(R) intravenous injection, 2013).

Carcinogenicity

    3.21.2) SUMMARY/HUMAN
    A) IRON DEXTRAN - There is a potential risk of carcinogenesis with the use of iron dextran.
    B) FERRIC CARBOXYMALTOSE AND FERUMOXYTOL - No carcinogenic testing has been completed.
    3.21.4) ANIMAL STUDIES
    A) SARCOMA - IRON DEXTRAN
    1) Sarcoma has developed in animals (e., rats, mice, rabbits and possibly hamsters) following large intramuscular doses of iron dextran (Prod Info INFeD(R) intravenous, intramuscular injection, 2008). Burns & Pomposelli (1999) suggested that intramuscular use of iron dextran may increase the risk of neoplasm formation (Burns & Pomposelli, 1999).
    2) At the time of this review, it is difficult to determine the potential risk as a human carcinogen due to the long latent period between administration and onset (Prod Info INFeD(R) intravenous, intramuscular injection, 2008).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Monitor serum electrolytes, CBC, serum iron levels, liver enzymes, renal function, PT/INR, and PTT in patients following a significant exposure.
    B) Peak serum iron levels can be delayed after administration. Elevated serum iron levels with no associated clinical evidence of toxicity have been reported after iron dextran overdose and may be present in the first 24 hours following ferumoxytol administration. Clinical signs and symptoms are more important than serum iron levels in assessing the need for treatment and chelation.
    C) IRON DEXTRAN may cause laboratory interference with serum bilirubin (falsely increased) and serum calcium (falsely decreased), as well as producing a brown color to the serum (5 mL or more).
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) Monitor CBC (hemoglobin, hematocrit), coagulation studies, electrolytes and liver and renal function studies and serial serum iron levels following a significant exposure.
    2) Intermittent monitoring of serum ferritin levels are indicated in patients following overdose or as indicated in patients with significant co-morbidity (renal failure, Hodgkin's disease, rheumatoid arthritis and to assess hepatic function).
    a) IRON DEXTRAN: Approximately 7 to 9 days after an intravenous dose of iron dextran, the serum ferritin levels will peak (Prod Info INFeD(R) intravenous, intramuscular injection, 2008). In one study, serum ferritin levels correlated with adverse hepatosplenic effects (Burns & Pomposelli, 1999).
    B) LABORATORY INTERFERENCE
    1) IRON DEXTRAN: May falsely elevate serum bilirubin values, while falsely decreasing serum calcium values (Prod Info INFeD(R) intravenous, intramuscular injection, 2008).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.2) DISPOSITION/PARENTERAL EXPOSURE
    6.3.2.1) ADMISSION CRITERIA/PARENTERAL
    A) Patients with severe symptoms despite treatment should be admitted.
    6.3.2.2) HOME CRITERIA/PARENTERAL
    A) A patient with an inadvertent exposure, that remains asymptomatic can be managed at home.
    6.3.2.3) CONSULT CRITERIA/PARENTERAL
    A) Consult a regional poison center or medical toxicologist for assistance in managing patients with severe toxicity or in whom the diagnosis is not clear.
    6.3.2.5) OBSERVATION CRITERIA/PARENTERAL
    A) Patients with a deliberate overdose, and those who are symptomatic, need to be monitored until they are clearly improving and clinically stable.

Monitoring

    A) Monitor serum electrolytes, CBC, serum iron levels, liver enzymes, renal function, PT/INR, and PTT in patients following a significant exposure.
    B) Peak serum iron levels can be delayed after administration. Elevated serum iron levels with no associated clinical evidence of toxicity have been reported after iron dextran overdose and may be present in the first 24 hours following ferumoxytol administration. Clinical signs and symptoms are more important than serum iron levels in assessing the need for treatment and chelation.
    C) IRON DEXTRAN may cause laboratory interference with serum bilirubin (falsely increased) and serum calcium (falsely decreased), as well as producing a brown color to the serum (5 mL or more).

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) Gastrointestinal decontamination is not recommended; administered via the parenteral route.

Range Of Toxicity

Summary

    A) TOXICITY: IRON DEXTRAN: An overdosage of iron dextran is unlikely to produce acute symptoms of iron toxicity. Adverse effects can be delayed up to 1 to 2 days, but have been reported following a single dose during therapeutic use. Doses of more than 500 mg have been associated with an increased risk of developing severe anaphylactoid reactions. A dose of 32 mL resulted in moderate toxicity in an adult; a child developed no symptoms following an intravenous dose of 1300 mg over a 48-hour period. FERRIC CARBOXYMALTOSE: A patient developed hypophosphatemic osteomalacia after receiving ferric carboxymaltose 4000 mg over 4 month. Following the discontinuation of ferric carboxymaltose, the patient recovered partially. Hemosiderosis with multiple joint disorder, walking disability and asthenia developed in a patient after receiving ferric carboxymaltose 18,000 mg over 6 months.
    B) THERAPEUTIC DOSES: Iron replacement is based on several indicators. The maximum daily dose is 2 mL of undiluted iron dextran.

Therapeutic Dose

    7.2.1) ADULT
    A) IRON DEFICIENCY ANEMIA
    1) IRON DEXTRAN
    a) Iron replacement is based on several indicators. The MAXIMUM daily dose should not exceed 2 mL undiluted iron dextran. The following is a list of factors needed to determine the iron requirements of an individual (Prod Info INFeD(R) intravenous, intramuscular injection, 2008):
    1) Blood volume - 65 mL/kg of body weight
    2) Normal hemoglobin (males and females) over 15 kg - 14.8 g/dL; 15 kg or less - 12.0 g/dL
    3) OTHER FACTORS: Iron content of hemoglobin (0.34%), hemoglobin deficit, and weight
    b) Based on the above data, a total dose may be calculated (Prod Info INFeD(R) intravenous, intramuscular injection, 2008):
    1) Dose (mL) = 0.0442 (Desired Hgb - Observed Hgb) x LBW (lean body weight in kg) + (0.26 x LBW)
    2) FERRIC CARBOXYMALTOSE
    a) PATIENTS WEIGHING 50 KG OR GREATER: 750 mg IV followed by 750 mg IV 7 or more days later; total cumulative dose not to exceed 1500 mg elemental iron. Administered as either undiluted slow IV push (rate, 2 mL/min) or by infusion. To administer by IV infusion, dilute up to 750 mg of iron in no more than 250 mL of NS to a final concentration of not less than 2 mg of iron per milliliter; administer over at least 15 minutes (Prod Info INJECTAFER(R) intravenous injection, 2013).
    b) PATIENTS WEIGHING LESS THAN 50 KG: 15 mg/kg IV followed by 15 mg/kg IV 7 or more days later; total cumulative dose not to exceed 1500 mg elemental iron. Administered as either undiluted slow IV push (rate, 2 mL/min) or by infusion. To administer by IV infusion, dilute up to 750 mg of iron in no more than 250 mL of NS to a final concentration of not less than 2 mg of iron per milliliter; administer over at least 15 minutes (Prod Info INJECTAFER(R) intravenous injection, 2013).
    B) IRON DEFICIENCY ANEMIA - RENAL IMPAIRMENT, CHRONIC
    1) FERRIC CARBOXYMALTOSE
    a) PATIENTS WEIGHING 50 KG OR GREATER: 750 mg IV followed by 750 mg IV 7 or more days later; total cumulative dose not to exceed 1500 mg elemental iron. Administered as either undiluted slow IV push (rate, 2 mL/min) or by infusion. To administer by IV infusion, dilute up to 750 mg of iron in no more than 250 mL of NS to a final concentration of not less than 2 mg of iron per milliliter; administer over at least 15 minutes (Prod Info INJECTAFER(R) intravenous injection, 2013).
    b) PATIENTS WEIGHING LESS THAN 50 KG: 15 mg/kg IV followed by 15 mg/kg IV 7 or more days later; total cumulative dose not to exceed 1500 mg elemental iron. Administered as either undiluted slow IV push (rate, 2 mL/min) or by infusion. To administer by IV infusion, dilute up to 750 mg of iron in no more than 250 mL of NS to a final concentration of not less than 2 mg of iron per milliliter; administer over at least 15 minutes (Prod Info INJECTAFER(R) intravenous injection, 2013).
    2) FERUMOXYTOL
    a) 510 mg IV at a MAX rate of 1 mL/sec (30 mg/sec) followed by a second dose given 3 to 8 days later (Prod Info FERAHEME(TM) injection, intravenous, 2009)
    C) IRON REPLACEMENT FOR BLOOD LOSS
    1) IRON DEXTRAN
    a) The following formula is used to calculate the necessary iron replacement needed to be the equivalent amount of iron present in blood loss (Prod Info INFeD(R) intravenous, intramuscular injection, 2008):
    1) Replacement iron (in mg) = Blood loss (in mL) x total hematocrit %
    b) NOTE: The manufacturer recommends dosing should be based on either the table provided or the use of the above formula and all patients should receive a TEST dose of 0.5 mL over 30 seconds prior to administration of a therapeutic dose (Prod Info INFeD(R) intravenous, intramuscular injection, 2008).
    7.2.2) PEDIATRIC
    A) IRON DEFICIENCY ANEMIA
    1) IRON DEXTRAN
    a) For children between 5 and 15 kg, the following dosing formula may be used:
    1) Dose (mL) = 0.0442 (Desired Hgb - Observed Hgb) x weight (kg) + (0.26 x weight)
    1) CAUTION: Iron dextran is NOT indicated in patients less than 4 months of age (Prod Info INFeD(R) intravenous, intramuscular injection, 2008).
    2) NOTE: The manufacturer recommends dosing should be based on either the table provided or the use of the above formula and all patients should receive a TEST dose of 0.5 mL over 30 seconds prior to administration of a therapeutic dose (Prod Info INFeD(R) intravenous, intramuscular injection, 2008).
    2) FERRIC CARBOXYMALTOSE
    a) The safety and efficacy of ferric carboxymaltose have not been established in the pediatric population (Prod Info INJECTAFER(R) intravenous injection, 2013).
    3) FERUMOXYTOL
    a) The safety and efficacy of ferumoxytol have not been established in the pediatric population (Prod Info FERAHEME(TM) injection, intravenous, 2009).

Minimum Lethal Exposure

    A) IRON DEXTRAN
    1) A minimum toxic dose has not been established; however, individuals have developed hypersensitivity including fatal anaphylactic reactions following therapeutic doses of iron dextran injection (Prod Info INFeD(R) intravenous, intramuscular injection, 2008).
    B) PEDIATRIC
    1) CASE REPORT (IRON DEXTRAN): A 4-year-old child died despite treatment with deferoxamine, hemodialysis, and hemoperfusion after inadvertent administration of iron dextran 3 grams (204 mg/kg) intravenously (Douidar & Snodgrass, 1989).

Maximum Tolerated Exposure

    A) IRON DEXTRAN
    1) An overdosage of iron dextran is unlikely to produce acute symptoms of iron toxicity; symptoms can be delayed up to 1 to 2 days following exposure (Prod Info INFeD(R) intravenous, intramuscular injection, 2008). Doses of more than 500 mg have been associated with an increased risk of developing severe anaphylactoid reactions (Burns & Pomposelli, 1999).
    2) Excess iron dextran required for the replacement of iron stores, may result in hemosiderosis, which could lead to hepatic and endocrine dysfunction (JEF Reynolds , 2000). Other possible symptoms related to overdose may be an increased risk of infection (Burns & Pomposelli, 1999).
    3) In a case-control study of patients on chronic dialysis who experienced adverse effects to intravenous iron dextran, the majority of events (113 of 163 {69%}) occurred with the first dose (ie, either as a maintenance dose or the first of a planned course of injections) (Fletes et al, 2001).
    B) CASE REPORTS
    1) ADULT - IRON DEXTRAN
    a) CASE REPORT: An adult was given 32 mL of iron dextran intravenously and within 24-hours developed meningitis-like symptoms (muscle cramps, bilateral frontal headaches, neck stiffness and photophobia). It was suggested that free iron crossed into the cerebrospinal fluid and was responsible for the symptoms that were observed (JEF Reynolds , 2000).
    b) CHRONIC THERAPY: A 63-year-old woman received a total dose of 52 grams iron dextran over 20 years intramuscularly. At the end of the treatment, her serum ferritin was markedly elevated and she had discolored subcutaneous lumps on her buttocks but no other clinical signs were reported (Saven & Beutler, 1989).
    2) PEDIATRIC - IRON DEXTRAN
    a) CASE REPORT: A 9-year-old female with Crohn's disease was inadvertently given 1300 mg of iron dextran via a TPN infusion over a 48-hour period; normal dose would have been less than 200 mg for the same infusion period. A serum iron level drawn 8 hours after the infusion was 1830 mcg/dL. The child developed no symptoms of toxicity, vital signs were stable, and laboratory values were within normal limits. Chelation was not performed, and serum iron levels returned to normal over the next three days (Rodgers et al, 1995).
    C) FERRIC CARBOXYMALTOSE
    1) CASE REPORT: A patient developed hypophosphatemic osteomalacia after receiving ferric carboxymaltose 4000 mg over 4 month. Following the discontinuation of ferric carboxymaltose, the patient recovered partially (Prod Info INJECTAFER(R) intravenous injection, 2013).
    2) CASE REPORT: Hemosiderosis with multiple joint disorder, walking disability and asthenia developed in a patient after receiving ferric carboxymaltose 18,000 mg over 6 months (Prod Info INJECTAFER(R) intravenous injection, 2013).

Toxicity Information

    7.7.1) TOXICITY VALUES
    A) LD50- (ORAL)MOUSE:
    1) 1 gm(Fe)/kg ((RTECS, 2000))
    B) LD50- (INTRAPERITONEAL)RAT:
    1) 3 g(Fe)/kg ((RTECS, 2000))

Pharmacology Toxicology

Pharmacologic Mechanism

    A) FERRIC CARBOXYMALTOSE
    1) Ferric carboxymaltose releases iron via a carbohydrate polymer that is complexed with colloidal iron (III) hydroxide (Prod Info INJECTAFER(R) intravenous injection, 2013).
    B) FERUMOXYTOL
    1) Ferumoxytol, a carbohydrate-coated iron oxide releases iron within vesicles in the macrophages of the liver, spleen, and bone marrow where it then enters into either the intracellular storage iron pool, or is transferred to plasma transferrin and is incorporated into hemoglobin by erythroid precursor cells (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    C) IRON DEXTRAN
    1) Iron dextran is a complex of ferric oxyhydroxide and a polyglucose that restores hemoglobin and depleted iron through the action of its iron component that forms hemosiderin or ferritin and transferrin by binding to protein moieties (Prod Info DEXFERRUM(R) Intravenous Solution, 2001).

Toxicologic Mechanism

    A) Although the mechanism leading to iron dextran-induced adverse effects remains unknown, the cause is speculated to be multifactorial (Burns & Pomposelli, 1999).
    B) ANAPHYLAXIS: Patients with a history of autoimmune or collagen vascular disease have an increased risk of anaphylaxis following iron dextran, which may be due to a direct toxic effect of iron on synovium by the generation of free radicals and peroxidation of lipids, or to reticuloendothelial system blockade, which can result in a secondary immune complex synovitis (Burns & Pomposelli, 1999).
    C) CARDIAC TOXICITY: In mice studies using intravenous iron dextran, it was found that iron loading can result in significant increases in total iron concentrations, alterations to glutathione peroxidase activity, and increases in cytotoxic aldehyde concentrations (a measure of free radical generation) in the heart, which may have a role in the development of myocardial damage (Bartfay et al, 1999). The authors also found that cellular damage occurred during iron loading.

Physicochemical

Physical Characteristics

    A) FERRIC CARBOXYMALTOSE is a dark brown, aqueous, isotonic colloidal solution (Prod Info INJECTAFER(R) intravenous injection, 2013).
    B) FERUMOXYTOL is an aqueous colloidal liquid that is black to reddish brown with an osmolality of 270 to 330 mOsm/kg (Prod Info FERAHEME(TM) injection, intravenous, 2009).
    C) IRON DEXTRAN is a dark brown, slightly viscous liquid (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014).

Ph

    A) FERRIC CARBOXYMALTOSE: 5 to 7 (Prod Info INJECTAFER(R) intravenous injection, 2013)
    B) FERUMOXYTOL: 6 to 8 (Prod Info FERAHEME(TM) injection, intravenous, 2009)
    C) IRON DEXTRAN: 5.2 to 6.5 (Prod Info INFeD(R) intravenous injection, intramuscular injection, 2014)

Molecular Weight

    A) FERRIC CARBOXYMALTOSE: 150,000 daltons (Prod Info INJECTAFER(R) intravenous injection, 2013)
    B) FERUMOXYTOL: 750 kilodaltons (Prod Info FERAHEME(TM) injection, intravenous, 2009)
    C) IRON DEXTRAN: Approximately 148,500 to 181,500 g/mole (Prod Info INFeD(R) IV, IM injection, 2009)

References

General Bibliography

    1) AMA Department of DrugsAMA Department of Drugs: AMA Evaluations Subscription, American Medical Association, Chicago, IL, 1992.
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    3) Anderson KJ & Rivers RPA: Desferrioxamine in acute iron poisoning (letter; comment). Lancet 1992; 339:1602.
    4) Anon: Breastfeeding and Maternal Medication. World Health Organization, Geneva, Switzerland, 2002.
    5) Bailie GR, Clark JA, Lane CE, et al: Hypersensitivity reactions and deaths associated with intravenous iron preparations. Nephrol Dial Transplant 2005; 20:1443-1449.
    6) Bartfay WJ, Butany J, & Lehotay DC: A biochemical, histochemical, and electron microscopic study on the effects of iron-loading on the hearts of mice. Cardiovas Pathology 1999; 8:305-314.
    7) Barton JC, Barton EH, & Bertoli LF: Intravenous iron dextran therapy in patients with iron deficiency and normal renal function who failed to respond to or did not tolerate oral iron supplementation. Am J Med 2000; 109:27-32.
    8) Bene C, Manzler A, & Bene D: Irreversible ocular toxicity from a single "challenge" dose of deferoximine. Clin Nephron 1989; 31:45-48.
    9) Benson B & Cheney K: Survival after a severe iron poisoning treated with high dose deferoxamine (DFO) therapy. Vet Hum Toxicol 1992; 34:329.
    10) Bielory L: Serum sickness from iron-dextran administration. Acta Haematol 1990; 83:166-168.
    11) Blake D, Winyard P, & Lunec J: Cerebral and ocular toxicity induced by deferoxamine. Q J Med 1985; 219:345-355.
    12) Blazevic A, Hunze J, & Boots JM: Severe hypophosphataemia after intravenous iron administration. Neth J Med 2014; 72(1):49-53.
    13) Boehnert M, Lacouture PG, & Guttmacher A: Massive iron overdose treated with high-dose deferoxamine infusion (Abstract). Vet Human Toxicol 1985; 28:291-292.
    14) Boelaert JR, de Locht M, & Van Cutsem J: Mucormycosis during deferoxamine therapy is a siderophore-mediated infection: in vitro and in vivo animal studies. J Clin Invest 1993; 91:1979-1986.
    15) Brophy GM, Bell R, Claassen J, et al: Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012; 17(1):3-23.
    16) Burns DL & Pomposelli JJ: Toxicity of parenteral iron dextran therapy. Kidney International 1999; 55 (suppl 69):119-124.
    17) Chamberlain JM, Altieri MA, & Futterman C: A prospective, randomized study comparing intramuscular midazolam with intravenous diazepam for the treatment of seizures in children. Ped Emerg Care 1997; 13:92-94.
    18) Chin RF , Neville BG , Peckham C , et al: Treatment of community-onset, childhood convulsive status epilepticus: a prospective, population-based study. Lancet Neurol 2008; 7(8):696-703.
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