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Special Alerts
Iron Dextran (Dexferrum®): Product Labeling Updated Emphasizing Risk of Anaphylactic-Type Reactions - October 2009
The Food and Drug Administration (FDA) and American Regent are notifying healthcare professionals of recent revisions made to the prescribing information for Dexferrum® (iron dextran injection). The changes pertain to the risk of anaphylactic-type reactions, including fatalities, which have occurred with parenteral administration of iron dextran. In particular, the boxed warning has been revised to recommend administering a test dose prior to the first therapeutic dose. Fatal reactions have been reported even in patients who tolerated the test dose; therefore all patients (regardless of an uneventful test dose) should be observed for signs/symptoms of anaphylactic-type reactions. Resuscitation equipment and trained personnel should be available during administration. The labeling also identifies patients who may be at an increased risk for anaphylactic-type reactions to iron dextran therapy. These patients include those with a history of drug allergy (including multiple drug allergies) and/or those receiving a concomitant ACE inhibitor. Additionally, the labeling revision highlights the difference in chemical characteristics between iron dextran products; iron dextran products are not clinically interchangeable.
For additional information, please refer to http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm186899.htm
ALERT: U.S. Boxed Warning
The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.
Medication Safety Issues
Sound-alike/look-alike issues:
Dexferrum® may be confused with Desferal®
Iron dextran complex may be confused with ferumoxytol
Pronunciation
(EYE ern DEKS tran KOM pleks)
U.S. Brand Names
Index Terms
Generic Available
No
Canadian Brand Names
Pharmacologic Category
Use: Labeled Indications
Treatment of iron deficiency in patients in whom oral administration is infeasible or ineffective
Use: Unlabeled/Investigational
Cancer-/chemotherapy-associated anemia
Pregnancy Risk Factor
C
Pregnancy Considerations
Adverse events have been observed in animal reproduction studies. It is not known if iron dextran (as iron dextran) crosses the placenta. It is recommended that pregnant women meet the dietary requirements of iron with diet and/or supplements in order to prevent adverse events associated with iron deficiency anemia in pregnancy. Treatment of iron deficiency anemia in pregnant women is the same as in nonpregnant women and in most cases, oral iron preparations may be used. Except in severe cases of maternal anemia, the fetus achieves normal iron stores regardless of maternal concentrations.
Lactation
Enters breast milk/use caution
Breast-Feeding Considerations
Trace amounts of iron dextran (as iron dextran) are found in human milk. Iron is normally found in breast milk. Breast milk or iron fortified formulas generally provide enough iron to meet the recommended dietary requirements of infants. The amount of iron in breast milk is generally not influenced by maternal iron status.
Contraindications
Hypersensitivity to iron dextran or any component of the formulation; any anemia not associated with iron deficiency
Warnings/Precautions
Boxed warnings:
• Anaphylactic-type reactions: See “Concerns related to adverse effects” below.
• Appropriate use: See “Other warnings/precautions” below
Concerns related to adverse effects:
• Anaphylactic-type reactions: [U.S. Boxed Warning]: Deaths associated with parenteral administration following anaphylactic-type reactions have been reported (use only where resuscitation equipment and personnel are available). A test dose should be administered to all patients prior to the first therapeutic dose. Anaphylactic and other hypersensitivity reactions have occurred even in patients who tolerated the test dose; observe for anaphylactic reactions during any iron dextran administration. A history of drug allergy (including multiple drug allergies) and/or the concomitant use of an ACE inhibitor may increase the risk of anaphylactic-type reactions. Adverse events (including life-threatening) associated with iron dextran usually occur more with the high-molecular-weight formulation (Dexferrum®), compared to low-molecular-weight (INFeD®) (Chertow, 2006).
• Delayed reaction: Delayed (1-2 days) infusion reaction (including arthralgia, back pain, chills, dizziness, and fever) may occur with large doses (eg, total dose infusion) of I.V. iron dextran; usually subsides within 3-4 days. May also occur (less commonly) with I.M. administration; subsiding within 3-7 days.
Disease-related concerns:
• Allergies/asthma: Use with caution in patients with a significant history of allergies or asthma.
• Cancer-associated anemia: In patients with cancer-related anemia (either due to cancer or chemotherapy-induced) requiring iron supplementation, the I.V. route is superior to oral therapy; I.M. administration is not recommended for parenteral iron supplementation.
• Cardiovascular disease: Use with caution in patients with pre-existing cardiovascular disease; iron dextran may exacerbate cardiovascular complications.
• Hepatic impairment: Use with extreme caution in patients with serious hepatic impairment.
• Renal disease/impairment: In patients with chronic kidney disease (CKD) requiring iron supplementation, the I.V. route is preferred for hemodialysis patients; either oral iron or I.V. iron may be used for nondialysis and peritoneal dialysis CKD patients. Avoid use during acute kidney infection.
• Rheumatoid arthritis: Use with caution in patients with rheumatoid arthritis; may exacerbate joint pain and swelling.
Special populations:
• Elderly: Anemia in the elderly is often caused by “anemia of chronic disease” or associated with inflammation rather than blood loss. Iron stores are usually normal or increased, with a serum ferritin >50 ng/mL and a decreased total iron binding capacity. I.V. administration of iron dextran is often preferred over I.M. in the elderly secondary to a decreased muscle mass and the need for daily injections.
• Pediatrics: Not recommended in children <4 months of age. Intramuscular iron dextran use in neonates may be associated with an increased incidence of gram-negative sepsis.
Dosage form specific issues:
• Product interchangeablility: Iron dextran products differ in chemical characteristics. The high-molecular-weight formulation (Dexferrum®) and the low-molecular-weight formulation (INFeD®) are not clinically interchangeable.
Other warnings/precautions:
• Appropriate use: [U.S. Boxed Warning]: Use only in patients where the iron deficient state is not amenable to oral iron therapy. Discontinue oral iron prior to initiating parenteral iron therapy.
• Carcinogenicity: Intramuscular injections of iron-carbohydrate complexes may have a risk of delayed injection site tumor development.
• Iron overload: Exogenous hemosiderosis may result from excess iron stores; patients with refractory anemias and/or hemoglobinopathies may be prone to iron overload with unwarranted iron supplementation.
Adverse Reactions
Frequency not defined. Note: Adverse event risk is reported to be higher with the high-molecular-weight iron dextran formulation.
Cardiovascular: Arrhythmia, bradycardia, cardiac arrest, chest pain, chest tightness, cyanosis, flushing, hyper-/hypotension, shock, syncope, tachycardia
Central nervous system: Chills, disorientation, dizziness, fever, headache, malaise, seizure, unconsciousness, unresponsiveness
Dermatologic: Pruritus, purpura, rash, urticaria
Gastrointestinal: Abdominal pain, diarrhea, nausea, taste alteration, vomiting
Genitourinary: Discoloration of urine
Hematologic: Leukocytosis, lymphadenopathy
Local: Injection site reactions (cellulitis, inflammation, pain, phlebitis, soreness, swelling), muscle atrophy/fibrosis (with I.M. injection), skin/tissue staining (at the site of I.M. injection), sterile abscess
Neuromuscular & skeletal: Arthralgia, arthritis/arthritis exacerbation, back pain, myalgia, paresthesia, weakness
Respiratory: Bronchospasm, dyspnea, respiratory arrest, wheezing
Renal: Hematuria
Miscellaneous: Anaphylactic reactions (sudden respiratory difficulty, cardiovascular collapse), diaphoresis
Postmarketing and/or case reports: Angioedema, tumor formation (at former injection site)
Drug Interactions
ACE Inhibitors: May enhance the adverse/toxic effect of Iron Dextran Complex. Specifically, patients receiving an ACE inhibitor may be at an increased risk for anaphylactic-type reactions. Management: Follow iron dextran recommendations closely regarding both having resuscitation equipment and trained personnel on-hand prior to iron dextran administration and the use of a test dose prior to the first therapeutic dose. Risk D: Consider therapy modification
Dimercaprol: May enhance the nephrotoxic effect of Iron Salts. Risk X: Avoid combination
Storage
Store at controlled room temperature.
Reconstitution
Solutions for infusion should be diluted in 250-1000 mL NS.
Compatibility
Stable in D5W, NS; variable stability (consult detailed reference) in TPN.
Compatibility when admixed: Compatible: Cyanocobalamin, netilmicin.
Mechanism of Action
The released iron, from the plasma, eventually replenishes the depleted iron stores in the bone marrow where it is incorporated into hemoglobin
Pharmacodynamics/Kinetics
Onset of action: I.V.: Serum ferritin peak: 7-9 days after dose
Absorption:
I.M.: 50% to 90% is promptly absorbed, balance is slowly absorbed over month
I.V.: Uptake of iron by the reticuloendothelial system appears to be constant at about 10-20 mg/hour
Excretion: Urine and feces via reticuloendothelial system
Dosage
I.M. (INFeD®; Z-track method should be used for I.M. injection), I.V. (Dexferrum®, INFeD®):
A 0.5 mL test dose (0.25 mL in infants) should be given prior to starting iron dextran therapy; total dose should be divided into a daily schedule for I.M., total dose may be given as a single continuous infusion. Individual doses of ?2 mL may be administered daily until calculated total dose is received.
Iron-deficiency anemia:
Children 5-15 kg: Should not normally be given in the first 4 months of life:
Dose (mL) = 0.0442 (desired hemoglobin - observed hemoglobin) x W + (0.26 x W)
Desired hemoglobin: Usually 12 g/dL
W = Total body weight in kg
Children >15 kg and Adults:
Dose (mL) = 0.0442 (desired hemoglobin - observed hemoglobin) x LBW + (0.26 x LBW)
Desired hemoglobin: Usually 14.8 g/dL
LBW = Lean body weight in kg
Iron replacement therapy for blood loss: Replacement iron (mg) = blood loss (mL) x hematocrit
Maximum daily dosage: Manufacturer's labeling: Note: Replacement of larger estimated iron deficits may be achieved by serial administration of smaller incremental dosages. Daily dosages should be limited to:
Children:
<5 kg: 25 mg iron (0.5 mL)
5-10 kg: 50 mg iron (1 mL)
Children ?10 kg and Adults: 100 mg iron (2 mL)
Total dose infusion (unlabeled): The entire dose (estimated iron deficit) may be diluted and administered as a one-time I.V. infusion.
Cancer-/chemotherapy-associated anemia (NCCN guidelines v.2.2010) (unlabeled use): Adults: I.V.: Test dose: 25 mg slow I.V. slow push, followed 1 hour later by 100 mg over 5 minutes; larger doses (unlabeled), up to total dose infusion (over several hours) may be administered. Low-molecular-weight iron dextran preferred.
Administration: I.M.
Note: Test dose: A test dose should be given on the first day of therapy; patient should be observed for 1 hour for hypersensitivity reaction, then the remaining dose (dose minus test dose) should be given. Resuscitation equipment and trained personnel should be available. An uneventful test dose does not ensure an anaphylactic-type reaction will not occur during administration of the therapeutic dose.
I.M. (INFeD®): Use Z-track technique (displacement of the skin laterally prior to injection); injection should be deep into the upper outer quadrant of buttock; alternate buttocks with subsequent injections. Administer test dose at same recommended site using the same technique.
Administration: I.V.
Test dose should be given gradually over at least 30 seconds (INFeD®) or 5 minutes (Dexferrum®). Subsequent dose(s) may be administered by I.V. bolus undiluted at a rate not to exceed 50 mg/minute or diluted in 250-1000 mL NS and infused over 1-6 hours (initial 25 mL should be given slowly and patient should be observed for allergic reactions); avoid dilutions with dextrose (increased incidence of local pain and phlebitis). Resuscitation equipment and trained personnel should be available. An uneventful test dose does not ensure an anaphylactic-type reaction will not occur during administration of the therapeutic dose.
Administration: I.V. Detail
pH: 4.2-7
Monitoring Parameters
Hemoglobin, hematocrit, reticulocyte count, serum ferritin, serum iron, TIBC; monitor for anaphylaxis/hypersensitivity reaction (during test dose and therapeutic dose)
Reference Range
Hemoglobin: Adults:
Males: 13.5-16.5 g/dL
Females: 12.0-15.0 g/dL
Serum iron: 40-160 mcg/dL
Total iron binding capacity: 230-430 mcg/dL
Transferrin: 204-360 mg/dL
Percent transferrin saturation: 20% to 50%
Test Interactions
May cause falsely elevated values of serum bilirubin and falsely decreased values of serum calcium. Residual iron dextran may remain in reticuloendothelial cells; may affect accuracy of examination of bone marrow iron stores. Bone scans with 99m Tc-labeled bone seeking agents may show reduced bony uptake, marked renal activity, and excess blood pooling and soft tissue accumulation following I.V. iron dextran infusion or with high serum ferritin levels. Following I.M. iron dextran, bone scans with 99m Tc-diphosphonate may show dense activity in the buttocks.
Patient Education
You will need frequent blood tests while on this therapy. If you have rheumatoid arthritis, you may experience increased swelling or joint pain; consult prescriber for medication adjustment. If you experience dizziness or severe headache, use caution when driving or engaging in tasks that require alertness until response to drug is known. Small frequent meals, frequent mouth care, sucking lozenges, or chewing gum may relieve nausea and metallic taste. You may experience increased sweating. Report acute GI problems, fever, respiratory difficulty, rapid heartbeat, yellowing of skin or eyes, or swelling of hands and feet. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Do not breast-feed.
Geriatric Considerations
Anemia in the elderly is most often caused by “anemia of chronic disease,” a result of aging effect in bone marrow, or associated with inflammation rather than blood loss. Iron stores are usually normal or increased, with a serum ferritin >50 ng/mL and a decreased total iron binding capacity. Hence, the anemia is not secondary to iron deficiency but the inability of the reticuloendothelial system to use available iron stores. I.V. administration of iron is often preferred over I.M. in the elderly secondary to a decreased muscle mass and the need for daily injections.
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Metallic taste.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
No information available to require special precautions
Mental Health: Effects on Mental Status
May cause dizziness
Mental Health: Effects on Psychiatric Treatment
None reported
Nursing: Physical Assessment/Monitoring
Assess results of laboratory tests regularly and patient for adverse reactions. Note that adverse response may occur some time (1-4 days) after administration. Assess patients with rheumatoid arthritis for exacerbated swelling and joint pain; adjust medications as needed.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Note: Strength expressed as elemental iron
Injection, solution:
Dexferrum®: 50 mg/mL (1 mL, 2 mL) [high-molecular-weight iron dextran]
INFeD®: 50 mg/mL (2 mL) [low-molecular-weight iron dextran]
References
Auerbach M, Ballard H, Trout JR, et al, “Intravenous Iron Optimizes the Response to Recombinant Human Erythropoietin in Cancer Patients With Chemotherapy-Associated Anemia: A Multicenter, Open-Label, Randomized Trial,” J Clin Oncol, 2004, 22(7):1301-7.
Auerbach M, Witt D, and Toler W, “Clinical Use of the Total Dose Intravenous Infusion of Iron Dextran,” J Lab Clin Med, 1988, 111(5):566-70.
Benito RP and Guerrero TC, “Response to a Single Intravenous Dose Versus Multiple Intramuscular Administration of Iron Dextran Complex: A Comparative Study,” Curr Ther Res Clin Exp, 1973, 15(7):373-82.
Chertow GM, Mason PD, Vaage-Nilsen O, et al, “Update on Adverse Drug Events Associated With Parenteral Iron,” Nephrol Dial Transplant, 2006, 21(2):378-82.
Lipschitz DA, “The Anemia of Chronic Disease,” J Am Geriatr Soc, 1990, 38(11):1258-64.
National Comprehensive Cancer Network® (NCCN), “Practice Guidelines in Oncology™: Cancer- and Chemotherapy-Induced Anemia Version 2.2010.” Available at http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf
National Kidney Foundation, “KDOQI Clinical Practice Guidelines and Clinical Practice Recommendations for Anemia in Chronic Kidney Disease,” available at http://www.kidney.org/professionals/KDOQI/guidelines_anemia/cpr32.htm and http://www.kidney.org/professionals/KDOQI/guidelines_anemia/ped32.htm.
Rizzo JD, Somerfield MR, Hagerty LK, et al, “American Society of Hematology/American Society of Clinical Oncology 2007 Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin,” Blood, 2008, 111(1):25-41.
International Brand Names
Lexi-Comp.com
Last full review/revision October 2009
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