Continuing Education Activity

Iron dextran is an injectable medication used in the management of iron deficiency anemia, particularly in patients who are unable to tolerate iron by mouth. It is in the class of medications referred to as iron replacement products. This activity outlines the indications, actions, and contraindications for iron dextran as a valuable agent in the treatment of iron deficiency anemia. Additionally, it will highlight the mechanism of action, adverse event profile, and other vital factors pertinent to members of the healthcare team.

Objectives:

• Describe the indications for therapy with iron dextran.
• Explain the mechanism of action of iron dextran
• Outline the potential adverse events and appropriate patient monitoring for these events during iron dextran administration.
• Review the importance of collaboration and communication amongst the interprofessional healthcare team to enhance the delivery of care and improve outcomes for patients treated for iron deficiency anemia with iron dextran.

Indications

Iron Dextran is an injectable low-molecular-weight ferric hydroxide complex indicated for patients with iron deficiency anemia where oral iron therapy is ineffective or poorly tolerated. It is particularly useful in iron deficiency resulting from excessive iron loss (e.g., hereditary hemorrhagic telangiectasia, excessive blood loss, etc.) or iron malabsorption (e.g., Crohn disease, celiac disease, inflammatory bowel disease, gastric bypass, etc.). Appropriate uses also include iron deficiency anemia resulting from menometrorrhagia, pregnancy, and surgical blood loss.[1]

Mechanism of Action

Iron dextran is ingested via endocytosis by the macrophages of the reticuloendothelial system. The fusion of the newly formed endosome with acidic lysosome results in the cleavage of the carbohydrate shell and the release of ferrous iron (Fe[2+]). Following release from its complex, Fe(2+) is shuttled across the endolysosomal membrane into the cytoplasm via divalent metal transporter 1 (DMT1), where it can be stored as a Fe-ferritin complex or get shuttled into the blood via ferroportin, a transmembrane protein. Once in the blood, Fe(2+) is immediately oxidized to ferric iron (Fe[3+]) by ceruloplasmin and subsequently bound by transferrin for transport to various sites throughout the body for utilization (i.e.,, to bone marrow for hemoglobin synthesis or to the liver for storage).[2][3] Hematologic responses of iron dextran may be observed within 3 to 10 days.  

Administration

There are currently two forms of low-molecular-weight iron dextran available on the market in North American. Both come as injectable solutions [intravenous (IV) or intramuscular (IM)] containing 50 mg/mL of elemental iron. The incidence of toxicity relative to high-molecular-weight preparations is lower with low-molecular-weight iron dextran. As per the manufacturer, a test dose of 25 mg (0.5 mL) followed by 1 hour of observation is necessary before administering the remainder of the calculated required dose to monitor for anaphylactoid reactions. Intramuscular injections should be administered to the upper outer quadrant of the buttock using the Z - track technique (lateral displacement of skin prior to injection).

• Total Dose (mL) = 0.0442 (Desired Hb – Observed Hb) x LBW + (0.26 x LBW)
• LBW = lean body weight; Hb = hemoglobin
• For adult males or male children over 15 kg (33 lbs): LBW = 50 kg + 2.3 kg / inch of patient height over 5 feet; normal Hb = 14.8 g/dL
• For adult females or female children over 15 kg (33 lbs): LBW = 45.5 kg + 2.3 kg / inch of patient height over 5 feet; normal Hb = 14.8 g/dL
• For children 4 months or older weighing 5-15 kg (11-33 lbs): use actual body weight (kg) instead of LBW; normal Hb = 12 g/dL

The total dose for iron replacement due to blood loss can be calculated as follows:

• Total dose (mg) = blood loss (mL) x Hct
• Daily Allowance:
• IV: 100 mg (2 mL) / day
• IM: Children over 4 months weighing less than 5 kg: 25 mg (0.5 mL) / day
  • Children over 4 months weighing between 5 and 10 kg: 50 mg (1 mL) / day
  • More than 10 kg: 100 mg (2 mL) / day

If total dose calculations exceed the daily allowance of administration, smaller incremental daily doses may be used until the patient achieves the total dose requirement. All doses require administration at a maximum rate of 50 mg (1 mL) per minute. No dosage adjustments are necessary for renal and/or hepatic impairment.

Off-label Clinical Use

Cancer / Chemotherapy-related anemia:

Auerbach's multicenter randomized clinical trial demonstrated that iron dextran (INFeD) administration is useful in optimizing the effects of recombinant human erythropoietin in patients with chemotherapy-associated anemia.[4] The researchers found two different administration approaches to be effective; 1) a 25 mg test dose followed by a 75 mg bolus once weekly for the first three weeks and 100 mg over 5 minutes once weekly thereafter until achieving the total calculated required dose, and 2) a total dose infusion diluted in 500 mL of normal saline and infused at a rate of 175 mL per hour.  

Total-dose infusion:

A retrospective analysis conducted by Auerbach found that a total dose of 1000 mg of iron dextran (INFeD) over 1 hour is safe and effective in patients with iron deficiency anemia.[5] Plummer et al. had similar findings in adolescents and children over 11 months old.[6] Finally, Mamula and colleagues found that a 2000 mg dose over 2 hours was safe and effective in pediatric and young adult patients.[7]

Considerations During Pregnancy

There is limited data regarding the safety of iron dextran during early pregnancy; therefore, Pavord et al. have suggested refraining from using intravenous iron dextran until the second or third trimesters.[8] Iron dextran may be found in trace amounts within breast milk; however, the World Health Organization (WHO) has indicated that iron dextran is compatible with breastfeeding.   

Adverse Effects

Although iron dextran has historically correlated with significant rates of adverse drug events, a retrospective review by Chertow et al. demonstrated that the majority of reported events were from the use of high-molecular-weight formulations of iron dextran, which are no longer available on the market.[9] In contrast to older formulations, few major adverse drug reactions (1 in 25000) have been reported with low-molecular-weight formulations currently available.[9] Although relatively rare, significant adverse drug reactions (2.47%) remain a concern for patient safety and may include death, anaphylactoid reaction (0.61%), allergic reaction, facial edema, pruritis, urticaria, back pain, tachycardia, cardiac arrest, chest pain, dyspnea, respiratory depression, hypotension, nausea, emesis, arthralgia, and diaphoresis.[10] 

Intramuscular infusions may additionally be associated with gluteal sarcomas and the following at the injection site: cellulitis, fibrosis, phlebitis, permanent skin discoloration, and localized myalgia.[1] Other adverse reactions include abdominal pain, diarrhea, dysgeusia, leukocytosis, lymphadenopathy, purpuric rash, fever, chills, disorientation, headache, numbness, paresthesia, seizure syncope, and wheezing.   

Contraindications

Administration is contraindicated in patients with a known hypersensitivity to iron dextran. Additionally, iron dextran is contraindicated in any form of anemia, which is not the result of iron deficiency. Co-administration with dimercaprol should be avoided as iron-dimercaprol chelates are especially toxic to renal tissue. Patients taking angiotensin-converting enzyme inhibitors may be at an elevated risk of developing adverse reactions. Additionally, caution is necessary when administering iron dextran to patients with any disease states that mimic known major adverse effects; disease states of concern include atopy, asthma, rheumatoid arthritis, and cardiovascular disease.

Monitoring

Patients should be monitored for anaphylaxis and hypersensitivity reactions for 1 hour following the administration of a 25 mg (0.5 mL) test dose. Test doses should be administered over 1 to 2 minutes. Other adverse reactions must also require monitoring throughout dose administration. Patients who do not experience an anaphylactoid reaction during the test dose may still be at risk for developing adverse drug reactions during the administration of the remainder of the calculated required dose. Anemia-related parameters including hematocrit, reticulocyte count, serum ferritin, serum iron, total iron-binding capacity (TIBC), and hemoglobin should be monitored following administration. TIBC, serum iron, transferrin saturation, and ferritin require monitoring for cancer or chemotherapy-related anemia.[11] Patients with chronic renal failure need more frequent monitoring as compared to patients without renal failure. 

Toxicity

The administration of iron dextran over the total calculated required dose might result in acute iron toxicity, metabolic acidosis, and hemosiderosis. Treatment of iron toxicity requires the removal of excess iron via intravenous iron chelation therapy with deferoxamine.

Enhancing Healthcare Team Outcomes

Appropriate knowledge, training, and cooperation of all interprofessional healthcare team members are vital to patient safety during the administration of iron dextran preparations. Proper evaluation regarding the appropriateness for parenteral iron (i.e., iron dextran) is necessary from prescribing clinicians. Consultation with pharmacists may help prevent errors, including appropriateness of drug use, dosage calculations, interactions, and pertinent dosage modifications. Medical professionals with training in anaphylactoid-type reactions should also be present during the administration of parental iron. Additionally, patient monitoring by nurses following administration will allow for the evaluation of therapeutic response and early detection of adverse drug reactions. Through proper training, open interprofessional communication, and cooperation, healthcare teams will be better equipped to facilitate the delivery of quality patient-centered care and improve overall patient outcomes. [Level 5]