Parenteral Iron: Pharmacology and Clinical Use

Parenteral iron in the form of iron and ammonium citrate had been used as early as 1872 for the treatment of anemia, but prohibitive toxic effects prevented widespread acceptance of this formulation [1, 2, 3]. Clinical use of parenteral iron accelerated after the introduction of improved and less toxic formations – iron saccharide in the 1940s and a short time thereafter iron-dextran [2, 3, 4].Iron-dextran is the only form of parenteral iron approved by the Food and Drug Administration for use in the United States. There has been a recent upsurge in the clinical use of parenteral iron following the introduction of recombinant human erythropoietin for anemia correction in patients with kidney failure [5]. In this review, the pharmacology and the clinical use of parenteral iron will be discussed.Iron-dextran is a colloidal suspension with particles of an average weight of 73 kD comprising a ferric oxyhydroxide (FeOOH) core, surrounded by chains of low molecular weight dextran (fig. 1) [6, 7]. The molecular weight of the dextran ranges from 5,000 to 7,000 daltons, and it has one side chain for every 21 glucose units. The low ratio of side chains of this dextran allegedly minimizes the chances of allergic reactions, as compared with dextrans that have a more complex structure.The size and molecular weight of the individual iron-dextran particle depends on the extent of polymerization. Also, the more polymerized the particles, the longer the shelf life of the iron-dextran preparation.Commercially available iron-dextran is a dark-brown solution with acidic pH (range 5.2–6.5) containing 50 mg of elemental iron per milliliter predominantly in the ferric state.In general, intravenous or intramuscular administration of iron is indicated when iron deficiency cannot be sufficiently treated by oral iron, or when for various reasons oral iron administration is impossible. Parenteral iron is being used extensively in erythropoietin-treated patients with chronic renal failure [5, 8], and its use in such patients will be discussed separate from nonrenal failure patients with iron deficiency.Patients with normal renal function who develop iron deficiency anemia can absorb enough of orally administered iron to replenish their iron stores [9, 10, 11]. In these individuals, the response to oral iron is equivalent to that following parenteral iron administration [9, 10, 11]. But, while it may take months of oral iron administration to replenish iron stores, it is usually accomplished in less time with parenteral iron [9, 10, 11].Parenteral iron is indicated for treatment of iron deficiency in patients with malabsorption syndromes such as sprue or following gastrointestinal surgery when absorption of oral iron is compromised. Also, parenteral iron may be used in patients receiving parenteral nutrition. Other indications include the rare instances of severe intolerance to oral iron – diarrhea, constipation, or vomiting may be so profound that parenteral iron is used or when oral iron administration has an adverse effect on inflammatory bowel disease. Rarely, it may be utilized in the iron-deficient patient who is noncompliant with oral iron regimen.In the United States and elsewhere, parenteral iron injections are advocated as the preferred route for anemia correction in chronic renal failure either alone or in combination with recombinant erythropoietin [12, 13, 14, 15, 16, 17]. When administered in combination with erythropoietin, parenteral iron injections purportedly enhance the response to erythropoietin, and consequently erythropoietin requirements may decline, resulting in substantial short-term cost savings [8, 13, 15].However, while there is partial understanding of iron metabolism in patients with normal renal function, the pathobiology of deranged iron metabolism in patients with chronic renal failure receiving erythropoietin is unclear [18, 19, 20, 21, 22, 23]. Commonly measured indices of iron availability (transferrin saturation, ferritin, total iron-binding capacity, and serum iron) are imperfect tools to diagnose iron deficiency in patients with chronic renal failure [18, 19, 20, 21, 22, 23]. Evaluation of iron stores using these indices may not accurately reflect the true iron status, making it difficult to diagnose iron deficiency in patients with chronic renal failure without resort to bone marrow biopsy [18, 19, 20, 21, 22, 23].In chronic renal failure, anemia is predominantly a result of diminished erythropoietin synthesis by diseased kidneys. Concomitant iron deficiency, resulting perhaps from a combination of inadequate intake and blood loss (gastrointestinal and during hemodialysis), is often cited as a cause of anemia in patients with chronic renal failure [24, 25, 26, 27, 28]. However, the magnitude or extent of gastrointestinal bleeding in patients with chronic renal failure has not been well quantified [24, 25, 26, 27, 28]. In fact, in several studies the incidence of positive Hemoccult stool tests in asymptomatic patients undergoing dialysis was less than 20% [26, 27, 28].In patients with normal renal function and a normal marrow, oral iron absorption in severe iron deficiency anemia may increase up to 50-fold, resulting in a two to three times increase in the rate of erythropoiesis [6, 7]. Gastrointestinal regulation of iron absorption limits the amount of orally administered iron that can be absorbed irrespective of the intensity of iron deficiency anemia [6, 7].In patients with renal failure receiving recombinant erythropoietin for anemia correction, several key questions regarding their iron metabolism remain unanswered: (1) What is the magnitude of increase in oral iron absorption induced by presumed iron deficiency and potent erythropoietic stimulus from intermittent bolus injections of recombinant erythropoietin? (2) Since chronic renal failure may be a chronic ‘acute-phase state’ [29, 30], is iron release from macrophages to marrow considerably reduced as compared with normal renal function (masquerading as absolute iron deficiency) [30]? (3) Finally, is oral iron absorption increased by stimulated iron deficiency but then limited by the ceiling imposed by gastrointestinal regulation?There are conflicting reports on the extent of oral iron absorption in patients with renal failure receiving erythropoietin, ranging from poor [31]to excellent [32]. Goch et al. [31], for example, in a single-center study, showed that uremic subjects with iron deficiency absorbed significantly less oral iron than did subjects with normal renal function and iron deficiency.In patients with normal renal function and presumed iron deficiency anemia, a rise in hematocrit after iron therapy is inferential support for the correctness of the diagnosis of iron deficiency [7]. However, based on available evidence [25, 33, 34], it is doubtful whether this thesis is true in patients with chronic renal failure. Both human [31, 33, 35, 36]and animal [37]studies show that the hematocrit may rise after intravenous iron administration even in the absence of anemia or iron deficiency. On the other hand, failure to respond with a rise in hematocrit following iron administration does not necessarily exclude iron deficiency in patients with chronic renal failure [12].In sum, the relative contribution of impaired iron utilization to what is currently termed iron deficiency in many erythropoietin-treated patients with renal failure may be underappreciated. This point is pertinent, since the aggressive use of large amounts of intravenous iron in ‘resistant’ patients is predicated on the thesis that they have absolute iron deficiency.The total dose requirement of iron can be estimated from the patients’ hemoglobin based on the following assumptions: (1) that 1 ml of red blood cells contains about 1 mg of iron; (2) that the iron content of hemoglobin is 0.34% by weight, and (3) that the total blood volume is about 65 ml/kg body weight [6, 7]. Thus, iron requirement = (desired hemoglobin – observed hemoglobin) × body weight in kilograms × 2.2. Iron-dextran should then be administered intramuscularly or intravenously until the total calculated amount has been reached. In the United States, the manufacturers recommend a maximum daily dose of 100 mg of undiluted iron-dextran, but the reality in many clinical settings in the USA is that higher daily doses (>500–1,000 mg) diluted with normal saline are being administered intravenously, and total-dose bolus administration is not prohibited in Europe [37, 38].Prior to the first therapeutic intramuscular administration, a 25-mg test dose of undiluted iron-dextran should be given and the patient observed for at least 1 h for acute side effects before the usual daily dose is given. Deep intramuscular injections into the mass of the upper outer quadrant of the gluteus muscle is recommended. Iron-dextran should not be injected into the arms. The Z-track technique of injection (displacement of skin laterally) is recommended to avoid injection into subcutaneous tissue and minimize discoloration of skin [6, 7]. Exercising the limb increases uptake of injected iron-dextran [6, 7].A test dose of 25 mg of iron-dextran should be administered over a minimum of 1 min prior to the first therapeutic dose. The patient should be observed for at least 1 h for acute side effects before proceeding with the first therapeutic dose at a rate not exceeding 50 mg (1 ml) per minute. Dilution with normal saline or 5% dextrose solution may increase the risk of local thrombophlebitis.The pharmacokinetics of parenteral iron was elucidated in studies that employed total-dose injections of 500 mg or greater of iron-dextran [2, 3, 9, 30, 35, 36, 39]. After intramuscular injection, mobilization of iron-dextran from the injection site is very slow [36]. About 50–70% of injected iron is absorbed within the first 72 h, while the balance may remain at the injection site for weeks to months [36]. Iron-dextran enters the blood via capillaries and lymphatics. In the plasma, it is phagocytosed by macrophages and dissociates slowly into iron and dextran [36]. Once the macrophage splits the complex into dextran and iron, the ionic iron reenters the plasma and is transported to the marrow normoblast receptor sites by transferrin for hemoglobin synthesis. Less than 2% of the iron-dextran complex is available for direct exchange to transferrin without processing by the macrophages.Some iron-dextran remains trapped within macrophages for months and may be gradually made available for incorporation into hemoglobin. Factors that determine the rate of release of iron-dextran from macrophages in patients with iron deficiency are not well known [9, 30, 35, 40, 41, 42]. Release of iron from macrophages slows after the initial 2–3 weeks following iron-dextran injection despite persistent anemia [9, 35].Prior to incorporation into red cell hemoglobin, iron-dextran is stored in liver, spleen, and bone marrow [3, 43, 44, 45]. There is very minimal loss of injected iron-dextran in the urine or in stool [3], and removal during hemodialysis is negligible [46].The pharmacokinetics of intravenous iron-dextran are described in table 1. Because of the sluggish release of iron from macrophages to marrow for erythropoiesis beyond the 3rd week, repeated intravenous infusions of iron-dextran may lead to a rise in hematocrit in subjects with adequate iron stores. This fact is instructive for the use of intravenous iron in erythropoietin-treated patients with renal failure in whom an increase in hematocrit after iron-dextran infusion is being widely advertised as confirmation of iron deficiency.Studies suggest that the larger iron-dextran particles may be preferentially trapped within macrophages [9, 35, 47], their egress being limited by their size, hence making them unavailable for hemoglobin synthesis.The response of iron deficiency anemia to parenteral iron depends on the severity of the iron deficiency and the presence of comorbid illnesses. Comorbid illnesses may delay release of iron from macrophages to the marrow and/or blunt erythropoiesis at the marrow level [42]. In patients with normal renal function and iron deficiency anemia, treatment with parenteral iron is accompanied by amelioration of symptoms such as headache, anorexia, and fatigue within a few days. An increase in the reticulocyte index may be noted by day 7 of therapy, and a rise in hematocrit may be observed within days thereafter.Following administration of a single total-dose intravenous infusion of iron-dextran in nonrenal failure patients, erythropoiesis increases by as much as 4.5 times the normal rate within the first 2 weeks, but quickly declines to about 1.5 times the normal rate thereafter, despite significant amounts of reticuloendothelial iron-dextran stores. This affirms the rate-limiting role of macrophages for iron delivery for erythropoiesis.Extent and rate of response to intravenous iron in patients with progressive chronic renal failure may depend on the amount of residual glomerular filtration, and thus the responsiveness may diminish as the patients progressively loose renal function [12, 30]. In fact, continued administration of parenteral iron in some patients with advanced chronic renal failure may fail to increase their hematocrit [12], thereby risking iron overload. Boddy et al. [25], employing a whole-body monitoring technique, reported reduced red cell incorporation of radio iron in patients with chronic renal failure.Evidence that impaired utilization of iron may be a key problem in chronic renal failure is the finding in a study of patients with chronic renal failure and anemia, that the cohort with mean creatinine clearance <20 ml/min failed to raise their hematocrit after 5 months of parenteral iron therapy, despite serum iron indices equivalent to their counterparts whose mean creatinine clearance was >20 ml/min [12]. Whether this proposition holds in patients with chronic renal failure on hemodialysis – that response to parenteral iron may depend on the amount of dialysis they receive – is unclear. Unfortunately, the effect of dialysis dose on the response to intravenous iron-dextran infusions was not stated in any of the studies on parenteral iron use in patients with end-stage renal failure [8, 13, 14, 15, 16].Local side effects of intramuscular injection include pain, muscle necrosis, and a dark discoloration of the skin that may persist for as much as 2 years. Intravenous infusions may cause thrombophlebitis, especially when diluted with 5% dextrose.Systemic reactions to iron-dextran have been reported to vary from none to 50%, and the frequency of systemic reactions is independent of the route of administration [6, 7, 48]. In a recent study of intravenous iron-dextran use in patients with end-stage renal disease, the incidence of side effects was 4.7% [48]and may be more likely in individuals with a history of multidrug allergy.The most dangerous systemic reaction to iron-dextran is anaphylactic shock which may lead to acute myocardial infarction or death [49, 50]. Anaphylactic reaction is infrequent, occurring in less than 1% of the patients. It is not dose dependent, may be precipitated by a few drops of diluted iron-dextran solution, and may occur after a negative test dose [51]. Therefore, iron-dextran should only be administered in a setting in which anaphylaxis can be quickly detected and treated.A typical anaphylactic reaction consists of dyspnea or choking sensation and diaphoresis within a few minutes of iron-dextran administration [6, 7]. Nausea and vomiting may follow, and progression to hypotension, respiratory failure, and cardiac arrest may be rapid. Once a reaction is noted, iron-dextran administration should be stopped, and epinephrine (0.5 ml of 1:1,000) given subcutaneously and saline administered if hypotension is present. Intravenous diphenylhydramine and/or methylprednisolone may also be given. Cardiopulmonary resuscitation should be started promptly if cardiac arrest occurs.It is postulated that anaphylactic reactions may be due to preformed antibodies to dextran or due to excess free divalent iron in the iron-dextran solution. Free divalent iron forms a weak and easily dissociable complex with dextran and may be more likely to be present in iron-dextran vials that have had a long shelf life. So, once anaphylaxis occurs, it is prudent to examine all the vials that came in the same batch.A list of reported acute side effects [48, 52, 53, 54, 55]following iron-dextran injection is shown in table 2.The majority of recent studies that examined the side effects of parenteral iron have focused exclusively on acute systemic reactions with inadequate attention to long-term side effects.Protracted intramuscular injections of parenteral iron has led to sarcomas at the site of injection in experimental animals. But, reported local malignancies at the site of injection of intramuscular iron in humans have varied from undifferentiated pleomorphic sarcoma to fibrosarcoma, casting doubt on a causal relationship with parenteral iron [6, 7, 56, 57, 58].On the other hand, there is ample evidence from both animal and human studies that increased iron levels in the serum following iron-dextran injections lead to impairment of the immune system [59, 60, 61, 62, 63, 64, 65]. Serum ferritin levels after intravenous iron-dextran approach levels seen with classic iron overload [66].High levels of iron in the blood following iron-dextran injection facilitate the growth of Escherichia coli in pigs [65], enhance the replication of Mycobacterium avium in human macrophages [62], impair opsonization and phagocytosis of bacteria [59, 64], and also predispose to bacterial sepsis.Iron-induced sepsis may be a relevant risk in patients with end-stage renal failure whose immune function is already compromised [59]. In fact, Collins et al. [61]in their recent study of 33,120 hemodialysis patients, found a 35% higher risk of death due to infection among those who had received intravenous iron for 4–6 months as compared with those who received iron for 1–3 months during the period of observation. There was no statistically significant difference between the two groups with regard to all-cause mortality. Furthermore, with many dialysis patients receiving as much as 2–4 g of iron-dextran annually, the potential exists for accumulation of large quantities of iron, as patients survive longer. Repeated doses of iron-dextran lead to increased hepatic deposition dialysis patients, and excess iron in the may facilitate infection studies in nonrenal failure patients suggest a higher risk of in patients with larger iron stores as compared with those with iron stores In hemodialysis patients, parenteral iron increases which may cell function and result in cell death as a iron-dextran within macrophages in the marrow or may that impair gastrointestinal absorption of iron thus setting up a that in more parenteral iron studies in patients with normal renal function have described with regard to risk of and excess body iron iron should be in any patient who has a systemic reaction to a test dose or to a injection of to such patients with systemic to iron dextran administration are and Parenteral iron should not be given to a with or iron-dextran has been used extensively in it be that it the and may be in the may occur with very amounts of diluted iron-dextran, and there is no evidence to suggest that it is less or more likely to occur with diluted Therefore, there should not be less for side effects with diluted iron-dextran that anaphylaxis following iron-dextran injection are not well In fact, anaphylaxis may occur even after a negative test dose. Therefore, doses be administered in a setting resuscitation is in of This is for hemodialysis or dialysis patients who are likely to receive their therapeutic doses of iron-dextran at after a negative test dose in a of iron from macrophages to the marrow is a rate-limiting in and a significant of administered iron-dextran is in especially after total-dose An increase in hematocrit may intravenous iron injection even in without iron deficiency is no evidence that total-dose infusion to a rise in hematocrit than daily doses in a patient with iron deficiency The rise in hematocrit following iron-dextran infusion is not to the administered dose in macrophages in the marrow after a large bolus dose may gastrointestinal absorption of orally administered This is in patients with for iron and may result in on parenteral understanding of the that the release of iron from reticuloendothelial cells to the marrow is nonrenal failure patients, iron deficiency a increase in the gastrointestinal absorption of It is unclear whether this increase in absorption of administered iron is in erythropoietin-treated patients with end-stage renal failure and iron deficiency. a single-center study that iron absorption is impaired in patients with renal failure, studies are to gastrointestinal absorption of iron and if it is impaired to determine whether it is due to local or impaired from the marrow or of the is that the aggressive use of parenteral iron in erythropoietin-treated patients with chronic renal failure is being by the that oral absorption of iron is not but is to support erythropoiesis induced by bolus injections of of the that lead to anaphylaxis is the of be if these are patient or to the or studies are especially in patients with chronic renal failure receiving large doses of iron-dextran to the between body iron and death due to disease, and