Continuing Education Activity

Iron dextran is an injectable complex comprising ferric hydroxide and a low-molecular-weight fraction of dextran. Iron dextran is an intravenous iron solution tailored to treat iron deficiency anemia. Oral iron therapy is frequently used for the treatment of iron deficiency anemia. However, certain patients either exhibit inadequate responses to oral iron or encounter difficulties in its administration. Iron dextran has been approved by the US Food and Drug Administration (FDA) for treating iron deficiency anemia in patients who are unresponsive to oral iron therapy or cannot tolerate it.

Injectable iron proves particularly beneficial in cases of iron deficiency stemming from conditions such as excessive iron loss (eg, hereditary hemorrhagic telangiectasia and significant blood loss) or iron malabsorption (eg, Crohn disease, celiac disease, inflammatory bowel disease, and gastric bypass). The appropriate application of iron dextran is recommended for iron deficiency anemia associated with menometrorrhagia, pregnancy, and surgical blood loss. This activity is tailored for healthcare professionals and summarizes indications, mechanisms of action, pharmacokinetics, administration protocols, and potential adverse effects associated with iron dextran therapy, emphasizing the pivotal role of an interprofessional healthcare team in optimizing patient outcomes while utilizing iron dextran. In addition, this activity highlights algorithms for making informed decisions in the clinical management of patients undergoing iron dextran treatment by providing insights into contraindications, monitoring strategies, and potential overdose risks of iron dextran.

Objectives:

• Identify appropriate candidates for iron dextran therapy based on their response to oral iron therapy, clinical indications, and iron deficiency anemia severity.

• Screen patients for conditions that may benefit from iron dextran therapy, including those with excessive iron loss or malabsorption syndromes.

• Assess patients for contraindications and potential adverse effects associated with iron dextran therapy, ensuring timely intervention if complications arise.

• Collaborate with other healthcare professionals to optimize patient outcomes through coordinated care and shared decision-making.

Indications

Oral iron therapy is frequently used for the treatment of iron deficiency anemia. However, certain patients either exhibit inadequate responses to oral iron or encounter difficulties in its administration.[1] Iron dextran is an injectable complex comprising ferric hydroxide and a low-molecular-weight fraction of dextran.[2] Iron dextran is an intravenous (IV) iron solution for treating iron deficiency anemia.

Injectable iron proves particularly beneficial in cases of iron deficiency stemming from conditions such as excessive iron loss (eg, hereditary hemorrhagic telangiectasia and significant blood loss) or iron malabsorption (eg, Crohn disease, celiac disease, inflammatory bowel disease, and gastric bypass). The appropriate application of iron dextran is recommended for iron deficiency anemia associated with menometrorrhagia, pregnancy, and surgical blood loss.[3]

FDA-Approved Indication

Iron dextran has been approved by the US Food and Drug Administration (FDA) for treating iron deficiency anemia in patients who are unresponsive to oral iron therapy or cannot tolerate it.[1][4]

Off-Label Use

Iron dextran is sometimes utilized off-label for restless leg syndrome (RLS). However, as per the RLS guidelines, there is insufficient evidence to determine the safety and efficacy of iron dextran for treating RLS.[5]

Mechanism of Action

After administering iron dextran, macrophages remove iron dextran from the bloodstream into the reticuloendothelial system (RES) via endocytosis.[6][7] The RES separates the components of iron dextran.[8] Iron binds to transferrin, an iron-binding protein that transports iron to the bone marrow.[9] The iron-transferrin complex binds to transferrin receptor 1 (TFR1) expressed on erythroid progenitor cells, and iron dissociates from transferrin.[10] Erythroid progenitor cells use iron to produce heme, a component of hemoglobin.[11] In the presence of erythropoietin, erythroid progenitor cells mature into erythrocytes.[12] Hemoglobin is a component of the mature erythrocytes that transport oxygen in the body. Red blood cell count increases about 7 days after iron dextran infusion.[1]

Pharmacokinetics

Iron dextran is a prodrug in the form of an iron carbohydrate complex.[13] Dextran is the carbohydrate component bound to iron and resembles a ferritin-iron complex.[14] Ferritin is an antigenic protein administered IV. Therefore, iron dextran is manufactured by replacing ferritin with a carbohydrate, rendering it a non-antigenic compound.[14]

Absorption: The absorption of iron dextran after intramuscular (IM) administration may take up to 3 weeks. Reticulocyte count peaks 5 to 10 days after iron dextran administration, and hemoglobin increases in 2 to 4 weeks.[13]

Distribution: Transferrin transports iron to the bone marrow for red blood cell production. The liver stores most of the excess iron in the form of ferritin or hemosiderin.[15]

Metabolism: The dextran component is degraded and excreted in the urine.[16] Iron is not actively excreted from the body.[15] Iron released from red blood cell destruction is recycled to form new red blood cells. Therefore, long-term iron infusions may result in iron accumulation in organs.

Elimination: Iron dextran has a dose-dependent half-life of 1 day to 3.5 days.[13] Since iron is continuously recycled in the body, the half-life does not represent elimination. This half-life represents the time until phagocytes take iron dextran from the plasma.[17]

Administration

Available Dosage Forms and Strengths

Currently, 2 forms of low-molecular-weight iron dextran are available in the North American market. Both are injectable solutions—IV or IM—containing 50 mg/mL of elemental iron.[2][14] Idiosyncratic reactions to iron dextran, such as hypotension and anaphylaxis, are not dose-dependent.[18] Therefore, an initial one-time 25 mg test dose of iron dextran is necessary before commencing iron dextran therapy for adults and children with a body weight of over 20 kg.

For children with a body weight of less than 10 kg, the test dose is 10 mg, whereas for children with a body weight of 10 to 20 kg, the test dose is 15 mg. After administering the test dose, healthcare professionals should monitor patients for 1 hour before administering the therapeutic dose. Anaphylactic reactions to therapeutic doses are observed in patients who tolerated the iron dextran test dose. Emergency medications should be readily accessible if the patient experiences an anaphylactic reaction.

IM injections are administered to the upper outer quadrant of the buttock using the Z-track technique, which involves laterally displacing the skin before injection.

Adult Dosage

The manufacturer recommends against exceeding 2 mL of iron dextran per day. If the calculated dose exceeds 2 mL, then daily doses of 2 mL or less should be administered until the total calculated dose is reached. 

Iron deficiency anemia dosing: According to the manufacturer, iron dextran dose is weight-based when treating iron deficiency anemia. The lean body weight (LBW) should be used in the formula unless the actual body weight is less than LBW. If the actual body weight is less than the LBW, then the actual body weight should be used. 

• Iron dextran's weight-based formula for iron deficiency anemia for adults and children with a body weight of more than 15 kg is:

Total dose (in mL) = 0.0442 (Desired hemoglobin – observed hemoglobin) x LBW + (0.26 x LBW)

• Iron dextran's weight-based formula for iron deficiency anemia for children with a body weight of 5 to 15 kg is:

Total dose (in mL) = 0.0442 (Desired hemoglobin – observed hemoglobin) x Weight + (0.26 x Weight)

Hemoglobin is in grams/deciliter (g/dL), and LBW or body weight is in kilograms (kg).

Iron replacement for blood loss dosing: According to the manufacturer, the total dose for iron replacement due to blood loss can be calculated as follows:

Total dose (in mL) = [blood loss (in mL) x hematocrit]/50 mg/mL

Specific Patient Populations

Renal impairment: Iron dextran does not require renal dosage adjustment.

Hepatic impairment: Iron dextran does not require hepatic dosage adjustment.

Pregnancy considerations: The American College of Obstetrics and Gynecology (ACOG) recommends oral iron as a first-line therapy for iron deficiency anemia during pregnancy.[19] IV iron may be used in patients who cannot tolerate or do not respond to oral iron. Data about the safety of IV iron during the first trimester is lacking. Iron dextran can be used during the second and third trimesters of pregnancy.[20]

Breastfeeding considerations: The World Health Organization (WHO) considers iron dextran compatible with breastfeeding.

Adverse Effects

Although iron dextran is historically correlated with significant rates of adverse drug events, a retrospective review demonstrated that most events were associated with the high-molecular-weight formulation of iron dextran, which is withdrawn from the US market.[21] A patient with a history of multiple drug allergies has a higher risk of allergy to iron dextran.[22] Most literature reports adverse effects for all IV iron preparations and are not agent-specific.[23][24]

The risk of infusion reactions and anaphylaxis varies by the rate of administration, dose, and stability of the IV iron formulation.[25] Infusion reaction, known as complement activation-related pseudoallergy (CARPA), is a major adverse event for all IV iron.[24] Labile iron does not bind quickly to transferrin, increasing CARPA risk.[25] CARPA is not life-threatening. Symptoms of CARPA include flushing, myalgias, arthralgias, back pain, and chest pressure.[25] Interrupting the infusion and restarting slower usually resolves mild infusion reactions.[24] More severe acute reactions with iron dextran are uncommon and include dyspnea, hypotension, chest pain, angioedema, neurological symptoms, and urticaria.[18][26] Fluids and steroids help manage moderate infusion reactions.[24] IM epinephrine and oxygen help manage severe reactions.[27] Antihistamines may worsen hypersensitivity reactions.

The currently available iron dextran is low-molecular-weight and carries a box warning for increased risk of anaphylaxis.[28][29] However, data to support the belief that low-molecular-weight iron dextran has the highest risk of anaphylaxis among injectable iron formulations is controversial.[28] A study showed that 2-hour infusions of 400 to 500 mg of iron sucrose had higher infusion-related side effects than iron dextran or lower-dose iron sucrose.[28] Therefore, patients requiring a high dose of iron need to receive the total dose of iron sucrose over multiple visits.

A commentary in the Kidney International Journal supports using low-molecular-weight dextran over iron sucrose when the patient requires a high dose of iron.[28] According to the National Kidney Foundation, patients can receive up to 1,000 mg of iron dextrose as a single dose, allowing the administration of a total dose infusion (TDI) in one visit.[28][30][18] The TDI is not FDA-approved because of the associated delayed dose-related arthralgias and myalgias.[28][18]

Although IV iron is thought to increase the risk of infections, a systematic review and meta-analysis showed no increased infection risk with IV iron formulations.[31][32] In addition, IV iron causes fewer gastrointestinal adverse events than oral iron.[24] 

Drug-Drug Interactions

Angiotensin-converting enzyme inhibitors decrease the breakdown of kinins and may increase the risk of anaphylaxis when administered with iron dextran.[33][33][33]

Dimercaprol binds to iron, forming a nephrotoxic complex. Coadministration of dimercaprol with iron dextran is not recommended.

Contraindications

Warnings and Precautions

The Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend against using IV iron in patients with systemic infections.[34] IV iron increases the risk of infections because IV iron increases non-transferrin-bound iron, making free iron readily available to promote pathogen replication.[35]

IV iron is contraindicated in the first trimester of pregnancy because studies confirming its safety in the first trimester are lacking.[36]  Factors that increase the likelihood of hypersensitivity reactions to IV iron are relative contraindications to all IV iron preparations and are not specific to iron dextran. The European Medicine Agency (EMA) identifies the rationale for the relative contraindications of IV iron.[36] 

• Factors that increase the incidence and severity of hypersensitivity reactions include previous reactions to IV iron, fast infusion rate, or mastocytosis.

• Factors that worsen the outcome of hypersensitivity reactions include severe respiratory or cardiac disease, elderly, beta-blockers, or angiotensin-converting enzyme inhibitors.

• Factors that increase the risk of hypersensitivity reactions include the history of allergy to other drugs, patient anxiety, or anxiety of staff administering the drug.

Monitoring

Vital signs and skin reactions are safety monitoring parameters.[37] The healthcare team should measure vital signs at baseline and monitor vital signs and skin reactions for 1 hour after administering a 25 mg (0.5 mL) test dose. Vital signs and skin reactions should also be monitored during and after therapeutic doses. As for efficacy, anemia-related parameters should be monitored, including hemoglobin, hematocrit, reticulocyte count, serum ferritin, serum iron, total iron-binding capacity (TIBC), and transferrin saturation.[38]

Toxicity

Transferrin is a protein that transports soluble, nontoxic iron in the body.[39] Transferrin saturation (TSAT) is a biomarker that indicates iron status. TSAT <20% suggests iron deficiency, and TSAT >40% indicates iron overload.[40] Free iron accumulates in the liver when TSAT reaches 60% to 70%. Free iron is toxic as it changes rapidly between divalent and trivalent forms, leading to chemical reactions and the production of oxygen radicals. This results in cellular, molecular, and organ damage.

Signs and symptoms of iron overload include nausea, vomiting, diarrhea, metabolic acidosis, hypotension, hepatic failure, and death.[41] The risk of iron overload increases when chronic administration of IV iron exceeds the amount of blood loss.[42][43] Iron chelating agents bind to iron accumulated in organs.[44] Iron bound to the chelator is excreted in the urine and feces. Iron chelators include IV or IM deferoxamine, oral deferiprone, and oral deferasirox.

Enhancing Healthcare Team Outcomes

Comprehensive knowledge, training, and collaboration among all interprofessional team members are essential for ensuring patient safety while administering iron dextran preparations. Clinicians must thoroughly evaluate the suitability of parenteral iron, including iron dextran. Pharmacists play a crucial role in error prevention by providing information on indications, dosage calculations, potential interactions, and relevant dosage adjustments. Clinicians must be present during the administration of parenteral iron to patients. Furthermore, nurses should diligently monitor patients following iron dextran administration to promptly identify any adverse drug reactions.

Most infusion reactions are mild and resolve by interrupting the infusion. In cases where pharmacological intervention is necessary, the interprofessional healthcare team may opt for IV fluids, corticosteroids, and IM epinephrine, depending on the reaction's severity.[45][27] Antihistamines are not recommended in this context.[27] By ensuring proper training, fostering open interprofessional communication, and promoting cooperation, healthcare teams enhance their ability to provide quality patient-centered care and ultimately improve overall patient outcomes.