Iron Deficiency Anemia

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U.S. Pharmacist

U.S. Pharmacist Continuing Education
ACPE Program No. 430-000-00-024-H01
This program provides 2.0 hours of credit (0.2 CEU).
Lesson Expires: April 30, 2002

This CE article is supported by an unrestricted educational grant from Schein Pharmaceutical, Inc
As a provider of pharmaceutical care, the pharmacist can play an important role in optimizing the use of iron supplements.

Iron deficiency anemia (IDA) occurs in approximately 25% of patients with anemia, affecting more than 500 million people worldwide, 20 million of whom live in the United States.1 Although its prevalence is highest in Third World countries, IDA remains a medical problem even in developed countries. It is most commonly found among children, women of childbearing age and pregnant women.

Iron performs many functions in the body. As hemoglobin, it carries oxygen to the tissues. As myoglobin, it facilitates oxygen use and storage in the muscles. As cytochromes, it transports electrons within the cells. Iron also is an integral part of enzymes in various tissues.


Overview of Iron2

Iron performs many vital functions in the human body. Iron as hemoglobin carries oxygen from the lungs to the various tissues. In the form of myoglobin, iron facilitates oxygen use and storage in the muscles. It serves as a transport medium for electrons within the cells in the form of cytochromes, and is an integral part of enzymes in various tissues. The human body’s iron balance is normally maintained by reutilization of iron from erythrocyte destruction and uptake of iron from the diet. In adult men, 95% of the iron required for the production of red blood cells (RBCs) is recycled from the breakdown of RBCs, and only 5% comes from the dietary sources.

The average adult body contains 3–5 g of iron. Sixty-five percent of body iron found in circulating RBCs and myoglobin may be classified as functional iron. The remaining body iron is stored primarily as ferritin, but some is stored as hemosiderin in hepatocytes and macrophages in the bone marrow, liver and spleen. A small amount of iron is associated with the iron transport protein, transferrin. Due to the toxicity associated with inorganic iron, transferrin is needed to transport iron through the blood. The total amount of iron in the body is determined by intake, loss, and storage of this mineral.

The normal Western diet provides 12–15 mg of iron daily, of which 5%–10% (1 mg) is absorbed. The amount of iron absorbed depends on amount of iron in the diet, its bioavailability, and the body’s requirement for iron. When iron requirements are increased—for example, in pregnancy, growth spurts or iron deficiency—the rate of absorption can increase to 25% of the amount ingested. The recommended dietary allowances for iron are given in Table 1.

Table 1
Recommended Dietary Allowances (RDA) for Iron2
Sex and age (years) RDA (mg/day)
Both sexes
< 1       
1–5          
6–10
10
Females
6–11       
12–49       
50 & older       
10
15
10
Males
6–11       
12–19       
20 & older   
10
12
10
Iron absorption takes place predominantly in the duodenum and upper jejunum; beyond this point intestinal bicarbonate elevates the pH, rendering iron insoluble. Iron bioavailability depends on dietary composition. The two major sources of iron in the diet are heme and nonheme iron, which are absorbed by different mechanisms. Heme iron, which accounts for approximately 40% of the total iron present in meat, poultry, and fish, is 2–3 times more bioavailable than nonheme iron. The remaining 60% of iron in meat, poultry and fish, and all the iron in vegetables products is present as nonheme iron. In contrast to the absorption of heme iron, absorption of nonheme iron is quite variable.3 Absorption of non-heme iron is increased by gastric acid and by other dietary components such as most meats and ascorbic acid. Absorption is decreased by dietary components that form insoluble complexes or chelates with iron, including polyphenols (in certain vegetables), tannin (in tea), phytates (in brans, grains and some vegetables), calcium (in dairy products) and antacids. Vegetarian diets are low in heme iron. This partially explains the high prevalence of iron deficiency anemia in Third World countries, where grain and vegetables compose a major portion of the normal diet, which lacks the more readily absorbed heme iron.

In the absence of blood loss, iron is excreted in small amounts. Only the amount of iron lost per day is absorbed, thus preventing iron overload. In adult males and postmenopausal females, approximately 1 mg of iron is lost daily through superficial gastrointestinal blood loss and desquamation of surface cells from the skin and from the gastrointestinal and urinary tracts. In menstruating females approximately 1.5–3 mg of iron is lost daily.

Clinical Presentation of Iron Deficiency Anemia

Patients with iron deficiency anemia may be asymptomatic or have vague, general signs and symptoms. Clinical presentation depends on the rapidity of development of the anemia, age, and cardiovascular status of the patient. Anemia of recent onset is most likely to present with cardiorespiratory symptoms, such as tachycardia, lightheadedness, and breathlessness.4 In cases of chronic, slow blood loss, there are adaptive mechanisms to the increasing anemia and patients can often tolerate extremely low levels of hemoglobin (e.g., <7 g/dL) with remarkably few symptoms. Most patients complain of lethargy, weakness and dyspnea. More unusual symptoms are headache, tinnitus and taste disturbance.5

Table 2
Differential Diagnosis of Hypochromic Anemias5
  IDA ACD Thalassemia Sideroblastic
anemias
Degree of anemia Any < 9 g/dL  Mild Any
MCV Decreases N or Decreases Decreases N, Decreases or Inceases
Serum ferritin    Decreases   N or Increases  N     Increases
TIBC Increases Decreases N N
Serum iron Decreases Decreases N Increases
Marrow iron Absent Present Present Present
More specific symptoms of iron deficiency anemia usually do not appear until the hemoglobin concentration falls below 8 or 9 g/dL. Up to 50% of patients with chronic iron deficiency anemia demonstrate pica, a craving for substances such as clay, ice or cornstarch. There are also epithelial changes, including koilonychia (spooning of nails), angular stomatitis and glossitis in 30% of the patients with chronic iron deficiency anemia.6 In children, chronic iron deficiency causes developmental delays and behavioral disturbances. In pregnant women, it increases the risk for a preterm delivery and delivering a low birth-weight baby. It also lowers the work capacity of adults.6

Diagnosis

Iron-deficient erythrocytes are hypochromic and microcytic. Hypochromic and microcytic anemia also occur in other disorders, such as anemia of chronic disorders (ACD), heme synthesis disorder (i.e., sideroblastic anemias) and globin synthesis disorder (i.e., thalassemia). In order to help differentiate the different types of anemia, evaluation should consist of measuring hemoglobin (Hgb) and/or hematocrit (Hct), mean cell volume (MCV), mean cell hemoglobin (MCH), reticulocyte count, serum iron, total iron binding capacity (TIBC), transferrin saturation (TSAT), serum ferritin and a stool sample for occult blood. The differentiation in diagnostic parameters of the hypochromic anemias is given in Table 2.

A low serum iron (<14 µmol/L in males and <11 µmol/L in females) and low ferritin levels (10 to 12 g/L) in the presence of an elevated TIBC (>75 µmol/L) is generally diagnostic of iron deficiency. The serum iron and the percent TSAT (serum iron x 100 divided by TIBC) reflect the amount of iron immediately available for hemoglobin synthesis. The serum ferritin reflects total body iron stores in healthy individuals.

Difficulty in diagnosis arises when more than one anemia is present—for example, iron deficiency and folate deficiency in malabsorption in a population where thalassemia is present, or in pregnancy, when the interpretation of red cell indices may be difficult.5

Table 3
Causes of Iron Deficiency Anemia2
Inadequate dietary intake
    • Decreased consumption of animal protein and ascorbic acid
    • Chronic alcoholism
    • Food faddism
    • Poor nutrition

Increased iron demands
    • Pregnancy
    • Infancy
    • Adolescence
    • Old age

Inadequate absorption from the GI tract
    • Malabsorption syndromes
    • Post-gastrectomy states
    • Certain drugs or foods

Blood loss
     • Trauma
    • Angiodysplasia
    • Hemorrhoids
    • Peptic ulcers
    • Gastritis
    • GI malignancies
    • Diverticular disease
    • Copious menstrual flow
    • Nosebleeds
    • Postpartum bleeding

Certain diseases
    • Rheumatoid arthritis
    • Malignancies

Serum ferritin <10–12 g/L is the earliest and most sensitive indication of iron deficiency. However, inflammatory illness, liver disease, and malignancies can elevate serum ferritin levels into low-normal range even in iron deficiency patients. This may not correlate with iron stores in the bone marrow.4

Anemia is not an absolute requirement for diagnosis. Some patients, for example, smokers, those with chronic pulmonary disease, and those with polycythaemia rubra vera, have elevated hemoglobin levels. When iron deficiency occurs in these patients, hemoglobin drops from the elevated level into the normal range. Therefore, MCV is the most sensitive red cell index of early iron deficiency anemia.7 TSAT <15% indicates iron deficiency anemia, but low TSAT values may also be present in inflammatory disorders. However, the TIBC helps to differentiate the diagnosis in these patients: a TIBC >400 g% suggests iron deficiency anemia, whereas values <200 g% usually represent inflammatory disease.4

Causes of IDA are listed in Table 3. In adults the major cause of iron deficiency is blood loss. Nutritional deficiency seldom is the sole cause of IDA. However, poor nutritional intake may facilitate the appearance of IDA if another factor is present.

Oral Iron Supplementation

Treatment of iron deficiency anemia necessitates correcting any underlying causes and implementing iron replacement. The oral route remains the first line of therapy for iron replacement due to its ease of administration, much lower cost and side effects profile compared with parenteral administration. Oral iron supplementation may provide sufficient iron to replace ongoing losses and support erythropoiesis. However, among its drawbacks are poor absorption and low patient compliance. It is not as efficacious as the IV iron since only a small fraction is absorbed and it may take 6 months to replace the needed iron. It is therefore not adequate therapy for functional iron deficiency, particularly in the presence of pharmacologic doses of erythropoietin (EPO).

Table 4
Iron Content of Common Oral Iron Products
PRODUCT     STRENGTH ELEMENTAL IRON     AMOUNT OF ELEMENTAL IRON    
Ferrous sulfate        300–325 mg        20%         60–65 mg
Ferrous sulfate, exsiccated  200 mg        30%         65 mg
Ferrous gluconate 300–325 mg 12%         37–39 mg
Ferrous fumarate 100 mg        33%         33 mg
Niferex-150
   Polysaccharide
   iron complex 		150 mg
   150 mg
In adults and pediatric patients with iron deficiency anemia, the recommended oral daily dose is 200 mg elemental iron and 2–3 mg/kg, respectively. Common oral iron products and their iron content can be found in Table 4. The following further decrease iron absorption:
• Food reduces amount of iron absorbed by as much as 50%. Hence, oral iron should be administered one hour before or two hours after meals for optimal absorption.
• Aluminum-based phosphate binders reduce absorption.
• Concurrent administration of antacids is not recommended. Oral iron preparations and antacids should be administered as far apart as possible.

Poor compliance of patients to an oral iron regimen is mainly attributed to an inability to tolerate side effects, particularly GI irritation, nausea and constipation. Patients’ failure to take the prescribed dose can also be because of inadequate understanding of the need for the medication. Inconvenient dosing and out-of-pocket cost have been cited as contributing to the compliance problem. Patients unable to tolerate oral iron may benefit by taking smaller, more frequent doses, starting with a lower dose and slowly increasing to the target dose, trying a different form or product, or taking the supplement at bedtime.8

Parenteral Iron Indications

Until recently, parenteral iron supplementation was limited to patients with documented iron deficiency in whom oral administration is unsatisfactory or impossible (see Table 5).3,9-11 Currently, with the approval of new IV iron products for the treatment of iron deficiency anemias in patients undergoing chronic hemodialysis or receiving erythropoietin, the above indication is changing. Candidates for parenteral therapy are those patients with iron deficiency anemia who did not satisfactorily respond to oral products either because of poor absorption or intolerance to side effects. There is inadequate iron absorption in short bowel syndrome, chronic bowel obstruction, inflammatory bowel disease, radiation enteritis and other conditions affecting the proximal small bowel. Patients who have undergone gastrectomy or vagotomy have higher gastric pH, decreasing the solubility of ferrous salts. Other indications for parenteral iron include chronic uncorrected bleeding, chronic renal failure requiring maintenance hemodialysis, long-term (2–3 months) parenteral nutrition, coagulation disorders, cancer-related anemia, and significant blood loss after major surgery. Published articles have documented the successful use of parenteral iron therapy in conjunction with EPO predialysis anemia,13 in patients who refuse blood transfusion and in whom oral iron administration is not possible or inadequate,13,14 and in the perisurgical setting.15

Table 5
Indications for Parenteral Iron Dextran
UNSATISFACTORY RESPONSE TO ORAL IRON REPLACEMENT
    • Poor absorption
    • Intolerance to side effects

MALABSORPTION SYNDROME
    • Short bowel syndrome
    • Chronic bowel obstruction
    • Inflammatory bowel disease
    • Radiation enteritis
    • Other conditions affecting the proximal small bowel

ACHLORHYDRIA
    • Gastrectomy
    • Vagotomy

OTHER
    • Chronic uncorrected bleeding
    • Chronic renal failure patients requiring maintenance hemodialysis
    • Long-term (2–3 months) parenteral nutrition
    • Coagulation disorders
    • Cancer-related anemia
    • Significant blood loss after major surgery
    • Patients who refuse blood transfusion
    • Predialysis anemia
    • Perisurgical setting

Available Parenteral Iron Products

Imferon, InFeD and DexFerrum are the iron dextran products that have been and currently are used in the U.S. InFeD became available in 1992 from Schein Pharmaceutical Inc., and Dexferrum, from American Regent Laboratories, Inc., was approved for use in 1995. Imferon was available from 1974 to 1991 and was the iron dextran used in two studies that reported serious side effects of parenteral iron dextran therapy.9,11

A recent addition to the parenteral iron armamentarium is sodium ferric gluconate complex in sucrose injection (Ferrlecit) from Schein Pharmaceutical, Inc., and R&D Laboratories, Inc. A comparison of Ferrlecit with iron dextran can be found in Table 6. Notable differences between these two products are:
• Ferrlecit does not have the “black box” warning that iron dextran has regarding anaphylactic-type reactions resulting from use of complexes of iron and carbohydrates.
• Polysaccharide (dextran) is present in iron dextran, but not in Ferrlecit. Polysaccharides, such as dextran, are thought to be the primary causative factor in the production of type I immediate hypersensitivity or anaphylactoid reactions from IV iron.
• Ferrlecit has no FDA-approved indication for IM injection.
• Presently, indication for use of Ferrlecit is limited to chronic hemodialysis patients with iron deficiency anemia who are receiving supplemental EPO.
• Ferrlecit test dose (2 mL) is diluted in normal saline 50 mL and infused over 60 min., whereas iron dextran test dose (0.5 mL) is given as an undiluted IV push over at least 30 secs.
• Ferrlecit treatment dose (125 mg/10 mL) is diluted in normal saline 100 mL and infused over 60 min. Iron dextran single IV dose
(100 mg/2 mL) is administered undiluted at a slow gradual rate not to exceed 1 mL/min.
• Iron dextran can be given via the total dose infusion (TDI), whereas TDI using Ferrlecit
has not yet been studied.
• Effect of Ferrlecit’s sucrose content (1,950 mg/125 mg Ferrlecit) on a patient’s renal function needs to be monitored, in light of the recent FDA letter alerting physicians to acute renal failure reportedly associated with administration of IV immune globulin (IVIG) products, which contain <1.6 g sucrose per gram of IVIG.18

Table 6
Comparison Between Sodium Ferric Gluconate and Iron Dextran
       SODIUM FERRIC GLUCONATE IRON DEXTRAN
MW Ferrlecit 350,000 daltons InFed 104,000 daltons
DexFerrum 267,0000 daltons
Composition Ferric oxide hydrate bonded to sucrose  chelates with gluconate in a molar rates of  2 Fe molecules to one gluconate molecule Complex of ferric hydroxide and dextran
Polysaccharide Content        Not significant Present
Sucrose Preservative Benzyl alcohol 9 mg/5 mL 20% (975 mg in 62.5 mg Fe) None
Indication     Treatment of iron deficiency anemia in patients undergoing chronic hemodialysis who are  receiving supplemental EPO therapy    Treatment of patients with documented iron deficiency in whom oral therapy is
unsatisfactory or impossible
Warning        No Black Box Warning hypersensitivity reactions Black Box Warning–
anaphylactic-type reactions
IM injection No Yes
IV injection Test Dose 25 mg (2 mL) diluted in 50 mL NS infused in 60 min.    25 mg (0.5 mL) undiluted
IVP over at least 30 sec
Usual Dose    125 mg (10 mL) diluted in 100 mL NS infuse over 60 min.   100 mg undiluted at a rate not to exceed 50 mg (1 mL) per min.
Treatment    8 doses x 125 mg = 1,000 mg  10 doses x 100 mg = 1,000 mg
Total Dose Infusion    Under investigation of amount of sucrose    Yes


Parenteral Iron Administration

Parenteral iron can be given by IM injection, single IV injection or infusion and total dose infusion. Before administration of the first dose of iron dextran or sodium ferric gluconate, a test dose should be given and the patient observed for at least one hour before giving the remaining portion of the initial dose. Since anaphylaxis and other hypersensitivity reactions have been reported in patients on iron dextran who had uneventful test doses or therapeutic doses, the manufacturers recommend that administration of subsequent test doses be considered during therapy. The test dose for adults is 25 mg.

The methods of administration of test doses of iron dextran and sodium ferric gluconate are different. The iron dextran test dose is given as an undiluted IV push over at least 30 seconds. The test dose of sodium ferric gluconate is diluted in normal saline 50 mL prior to infusion over one hour.
Intramuscular Injection: As the original route of administration, the IM injection of iron dextran is infrequently used since it has been identified with several disadvantages, including (1) considerable pain and discomfort at the injection site, (2) staining of the skin, (3) bleeding, (4) formation of sterile abscesses, (5) tissue necrosis and atrophy, and (6) sarcoma formation.

Table 7
Iron Dextran Protocol in Patients Receiving EPO for Treatment of Anemia in CRF
TSAT <20% and/or  Ferritin <100 ng/mL 
• 100 mg Fe IV at every hemodialysis x 10 doses
• Measure TSAT, serum ferritin, Hgb/Hct after 2 weeks
• If TSAT & serum ferritin are the same, give another course of IV iron: 100 mg x Fe IV at every hemodialysis x 10 doses or 100 mg per week x 10 weeks
TSAT > or = 20% and
Ferritin > or = 100 ng/mL      
  
• 50–100 mg Fe IV once a week for 10 weeks to attain target Hct 33%–36% (Hgb 11–12 g/dL)
• IV Fe can be given 3x per week to once every 2 weeks to provide 500–1000 mg Fe within 10 weeks
TSAT > or = to 50% and/or Ferritin > or = 800 ng/mL • Hold IV iron for up to 3 months
• Remeasure Fe parameters
TSAT <50% and
Ferritin <800 ng/mL		 • Restart IV iron at dose reduced by 1/3 to 1/2
Optimal Hgb/Hct and iron stores • IV iron 25–100 mg per week for maintenance
To minimize local complications and avoid leakage into the subcutaneous tissue, the Z-track technique is recommended. The IM injection is given in the upper quadrant of the buttock and the site should be alternated daily for multiple injections.
Single IV Injection: Daily doses of iron dextran and sodium ferric gluconate can be given IV: iron dextran as an undiluted injection given by slow IV at 50 mg/min, and sodium ferric gluconate administered as an infusion in normal saline over 30 min (62.5 mg) or one hour (125 mg). The rate of administration of sodium ferric gluconate of 2.1 mg/min should not be exceeded.

Iron dextran has also been used as an additive to parenteral nutrition when the patient is on long-term nutritional support, i.e., at least 2–3 months. Compatibility guidelines should be developed concerning three-in-one admixtures since surface charge of lipid particles can be neutralized, causing cracking or creaming of the lipid component, and recommendations vary between lipid emulsion manufacturers. One institution allows addition of 2 mg iron dextran per bag of lipid-containing TPN and 10 mg in non-lipid-containing bags.10 However, it should be noted that manufacturers of iron dextran and sodium ferric gluconate state that these products should not be added to parenteral nutrition solutions.
Total Dose Infusion: Instead of small daily injections, total iron replacement given by total dose IV infusion has been found to be as effective and safe, less time-consuming, and convenient. By this method, the total calculated iron replacement dose is diluted in 250 to 1,000 mL of normal saline. Dilution with 5% dextrose injection is reportedly associated with a higher incidence of local pain. A test dose of 25 mg should be given slowly over 5 minutes. In the absence of adverse reactions, the remaining dose is infused over 4–6 hours. After infusion, the vein is flushed with normal saline.10,17

Parenteral Iron Dosage

For patients with iron deficiency anemia, the replacement dose, i.e., the amount of iron dextran needed to restore hemoglobin to normal and to replete iron stores, is calculated as follows:19

Adults & patients weighing >15 kg:
Dose (mg) = 0.3 x (Wt in lbs) x [100 - (Hgb x 100)/14.8]
where 14.8 is normal mean Hgb.
Children <15 kg:

Dose = 0.3 x (Wt in lbs) x [100 - (Hgb x 100)/12]
To replace blood lost on an intermittent or repetitive basis, iron dextran dose is calculated as follows:

    Replacement iron (mg) = blood loss in mL x hematocrit in decimal.

National Kidney Foundation-DOQI Clinical Practice Guidelines recommend that dosing of IV iron for pediatric patients be adjusted according to weight. For pediatric hemodialysis patients, each dose of a 10-dose course should be 25 mg, 50 mg and 100 mg for a <10 kg, 10–20 kg and >20 kg patient, respectively. For pediatric predialysis and peritoneal dialysis patients, each dose of a 10-dose course should be 125 mg, 250 mg and 500 mg for a <10 kg, 10–20 kg and >20 kg patient, respectively.

The Anemia Work Subgroup iron dextran protocol proposed in the NKF-DOQI Clinical Practice Guidelines (Table 7) is recommended for patients receiving EPO in the treatment of anemia in chronic renal failure (CRF).

The dose for sodium ferric gluconate for repletion treatment of iron deficiency in hemodialysis patients is 125 mg (10 mL) per dose for a total cumulative dose of 1,000 mg elemental iron, given in 8 sequential dialysis treatments.

Parenteral Iron ADRs

The overall incidence of adverse events from parenteral iron dextran therapy is about 26%, but the majority of such events are self-limited and mild.3,8,10,11,17 More severe symptoms occur in 3% of patients. Life-threatening/serious acute reactions occur in 0.65% of non-dialysis patients and 0.7% of dialysis patients.

Local reactions are more common after IM injection and can be seen at the administration site. These include pain, brown staining of the skin, sterile abscesses, necrosis, atrophy and sarcoma formation.

Adverse effects of parenteral iron dextran use can be classified as local or systemic. Systemic reactions can either be immediate (occurring within 5 minutes of injection) or delayed (starting within 24–48 hours after infusion and subsiding after 3–4 days).

Immediate reactions may range in severity from mild, transient to life-threatening, anaphylactic.

Examples of delayed reactions are myalgia, arthralgia, phlebitis, backache, lymphadenopathy, moderate to high fever, chills, dizziness, headache, malaise, nausea and/or vomiting. There is some evidence that dosage reduction and increasing the interval between doses may reduce the frequency and severity of delayed reactions. ADR incidence associated with the use of sodium ferric gluconate is low (<5%). However, there is a low exposure rate of patients from which these observations were made: North American studies involved 159 patients and European studies involved 226 patients.22
Among the ADRs reported were:
Faich and Strobos20 assessed the safety profile of sodium ferric gluconate versus iron dextran by using adverse events (numerator) and usage (denominator) reported to the World Health Organization, German Health Bureau, the manufacturer (sodium ferric gluconate), and the United States (iron dextran). For iron dextran, the acute allergic reaction rate was 8.7 cases per million doses from 1976 to 1996. Anaphylactic reaction incidence for sodium ferric gluconate from 1992 to 1996 was 3.3 cases per million doses. In an editorial, Matzke21 pointed out that the risk of anaphylactic reaction from iron dextran decreases to approximately 6 cases per million doses. He also observed that the absolute accuracy of these data, plus the 15.8% (31 deaths) fatality rate for iron dextran versus zero for sodium ferric gluconate, may be affected by the methodology of the voluntary adverse drug reaction reporting systems in Germany and in the U.S. However, he states that sodium ferric gluconate, with its better adverse event profile, will benefit U.S. patients who have a history of severe reactions to iron dextran.

Certain patients are at increased risk of developing adverse effects to parenteral iron dextran. Patients with rheumatoid arthritis and other inflammatory conditions may be at particular risk for delayed reactions and anaphylaxis. This may be prevented or minimized by administration of nonsteroidal drugs and IV methylprednisolone. Malnourished patients on parenteral iron therapy may have increased susceptibility to bacterial infection since excessive amount of circulating iron may stimulate bacterial growth.

Iron TDI (total dose infusion) has the disadvantage of exacerbating arthritic symptoms in patients with preexisting inflammatory joint disease. Patients with confirmed infections who received TDI of iron dextran also tended to have a higher incidence of immediate and delayed reactions. It is therefore recommended that iron TDI not be given in the presence of suspected or confirmed infection. Patients with a history of allergy, multiple drug allergies and asthma are more susceptible to the adverse effects of iron dextran, so this therapy should be used with caution in these patients.

Parenteral Iron and Erythropoietin Therapy

In addition to the NKF-DOQI Clinical Practice Guidelines for the Treatment of Anemia of Chronic Renal Failure, there are an increasing number of publications documenting that effective erythropoiesis requires both iron and EPO. These clinical situations include cancer-related anemia, patients who refuse blood transfusion,3,9 massive blood loss after major surgery,12 predialysis anemia8 and the perioperative setting.11 Iron supplementation is essential to assure adequate response to EPO because iron demands by the erythroid marrow frequently exceeds the amount of iron available for hemoglobin
Adverse drug reaction incidence associated with the use of sodium ferric gluconate is low (<5%).
synthesis and iron stores. EPO supplementation stimulates erythropoiesis to greater than normal levels, often leading to functional iron deficiency. Unlike absolute iron deficiency, in which iron stores are depleted and iron delivery to the erythroid marrow is impaired, functional iron deficiency results when a greater amount of iron is needed to support hemoglobin synthesis than can be released from the iron stores. EPO therapy without sufficient iron supplementation is like “pouring EPO down the drain.”
The following information was taken from the NKF-DOQI guidelines on iron support:
In the perioperative setting, iron availability is critical to optimize EPO response when EPO is given to increase red cell mass and stimulate sufficient, rapid regeneration of blood lost at the time of surgery, thus avoiding autologous blood donation and/or homologous transfusion. The study by Rutherford et al.15 showed these results in a randomized trial involving 24 healthy, iron-replete men in a simulated perisurgical setting. Certain questions, however, need to be answered. For non-renal patients, how much iron should be given to patients receiving EPO? How should they receive it? What route and what dosing schedule? Further study is needed on the concurrent use of IV iron with EPO in non-renal situations.

Role of the Pharmacist in Iron Supplementation
As a provider of pharmaceutical care, the pharmacist can play an important role in optimizing the use of iron supplements to attain positive patient outcomes while minimizing adverse effects and other medication-related problems. Since the oral route is still the easiest and least expensive mode of taking iron preparations, the pharmacist can assist the patient in getting the most out of his/her oral regimen by doing the following:
As the initial route of parenteral administration, IM injection of iron dextran is not often used because it causes considerable pain and discomfort and due to other disadvantages. Ferrlecit does not have an approved indication for IM injection. The IV route, therefore, becomes the preferred parenteral method of providing patients with the needed iron. The pharmacist can provide patients with two important services in this regard: (1) ensuring that the medication order is appropriate and (2) preventing, minimizing and monitoring adverse effects of parenteral iron.

In order to assess the appropriateness of a particular medication order for parenteral iron, the pharmacist should be knowledgeable in the following areas: Last, the pharmacist should see to it that patients receiving EPO also receive adequate iron supplementation, since effective erythropoiesis requires both iron and EPO. There are also an increasing numbers of published articles involving hemodialysis patients showing that IV iron supplementation improves responsiveness to EPO and may reduce the amount of EPO needed to achieve and maintain target Hct/Hgb.

REFERENCES
  1. Burns DL, Mascioli EA, Bistrian BR. Parenteral iron dextran therapy: A review. Nutrition. 1995;11:163-168
  2. Recommendations to Prevent and Control Iron Deficiency in the United States. MMWR. 1998;47(3):1-29
  3. Kumpf VJ. Parenteral iron supplementation. Nutr Clin Prac 1996;11:139-146
  4. Sproat TT. Anemias. In: Dipiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM, editors. Pharmacotherapy: A Pathophysiological Approach. 4th ed. Connecticut: Appleton & Lange; 1999. p 1531-1548.
  5. Frewin R, Henson A, Provan D. ABC of clinical haematology: iron deficiency anemia. BMJ. 1997;314(7077):360-3
  6. Walker ARP. The remedying of iron deficiency: what priority should it have? Br J Nutr. 1998;79:227-235
  7. Arthur CK, Ishister JP. Iron deficiency: misunderstood, misdiagnosed and mistreated. Drugs. 1987;33:171-182
  8. National Kidney Foundation Study Group: NKF-DOQI Clinical Practice Guideline for the Treatment of anemia of chronic renal failure.
    Am J Kidney Dis. 30:S192-S237, 1997 (suppl 3)
  9. Hamstra RD, Block MH, Schocket AL. Intravenous iron dextran in clinical medicine. JAMA. 1980;243(17):1726-1731
  10. Burns DL, Mascioli EA, Bistrian BR. Parenteral iron dextran therapy: A review. Nutrition. 1995;11:163-168
  11. Kumpf VJ, Holland EG. Parenteral iron dextran therapy. Ann Pharmacother. 1990;24:162-166
  12. Silverberg DS et al. Intravenous iron for the treatment of predialysis anemia. International Society of Nephrology. 1999;S79-S85.
  13. Dudrick SJ et al. Rapid restoration of red blood cell mass in severely anemic surgical patients who refuse transfusion. Arch Surg. 1985;120:721-727.
  14. Mann MC, et al. Management of the severely anemic patient who refuses transfusion: lessons learned during the care of a Jehovah’s Witness. Ann Intern Med, 1992;117:1042-1048
  15. Rutherford CJ, et al. Efficacy of different dosing regimens for recombinant human erythropoietin in a simulated perisurgical setting: the importance of iron availability in optimizing response. Am J Med. 1994;139-145
  16. Goodnough LT, Merkel K. Parenteral iron and recombinant human erythropoietin therapy to stimulate erythropoiesis in patients undergoing repair of hip fracture. Hematology. 1996;1:163-166
  17. Auerbach M et al. Clinical use of the total dose intravenous infusion of iron dextran. J Lab Clin Med. 1998;111:566-70
  18. Epstein JS, Zoon KC. Important Drug Warning. Department of Health and Human Services. September 29, 1999
  19. McEvoy GK, ed. American Hospital Formulary Service (AHFS) Drug Information. Bethesda, MD: American Society of Health System Pharmacists Inc, 1995:1237-42
  20. Faich G, Strobos J. Sodium ferric gluconate complex in sucrose: safer intravenous iron therapy than iron dextrans. Am J Kidney Dis. 1999;33(3):464-470.
  21. Matzke GR. Editorial. Am J Kid Dis, 1999;33(3):595-597.
  22. Ferrlecit Package Insert. Schein Pharmaceutical, Inc, and R&D Laboratories, Inc. 1998.
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