Find synonyms Find exact match
Disclosures: Stanley L Schrier, MD Nothing to disclose. Michael Auerbach, MD, FACP Nothing to disclose. William C Mentzer, MD Equity Ownership/Stock Options: Johnson & Johnson [Anemia (Erythropoietin)]. Stephen A Landaw, MD, PhD Employee of UpToDate, Inc. Employee (Spouse): Mass Medical Society (New England Journal of Medicine).
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is required of all authors and must conform to UpToDate standards of evidence.
INTRODUCTION — The management of adults with anemia due to iron deficiency, including the relevant diagnostic and therapeutic issues as well as the choice of iron preparation, will be discussed here.
The causes and diagnosis of iron deficiency are discussed separately, as is the treatment of iron deficiency in infants and young children and adolescents. (See "Causes and diagnosis of iron deficiency anemia in the adult" and "Iron deficiency in infants and young children: Treatment" and "Iron requirements and iron deficiency in adolescents".)
The uses of iron preparations for the treatment of functional iron deficiency in patients with chronic kidney disease as well as malignancy being treated with erythropoietin are specialized subjects and are presented separately. (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients" and "Use of iron preparations in hemodialysis patients" and "Diagnosis of iron deficiency in chronic kidney disease" and "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Iron monitoring and supplementation'.)
MANAGEMENT OVERVIEW — The usual presenting symptoms in adults, as seen in current practice, are primarily due to anemia, and include weakness, headache, irritability, and varying degrees of fatigue and exercise intolerance. However, many patients are asymptomatic and may recognize that they had fatigue, weakness, exercise intolerance, pagophagia (ice craving, a form of pica), or restless legs syndrome only after successful treatment with iron. (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Clinical manifestations'.)
Similar symptoms, especially fatigue and exercise intolerance, can also be present in subjects who are iron deficient but not anemic (ie, those with normal henmoglobin levels and low serum ferritin levels). (See 'Treatment of fatigue in nonanemic subjects' below.)
Public health aspects — More than a quarter of the world's population is anemic, and about one-half of this burden is a result of iron deficiency anemia, being most prevalent among preschool children and women . The prevention and treatment of iron deficiency is obviously a major public health goal, especially in low- and middle-income countries, although the various aspects of this issue are complex and beyond the scope of this review . (See "Iron deficiency in infants and young children: Screening, prevention, clinical manifestations, and diagnosis", section on 'Prevention of iron deficiency' and "Iron requirements and iron deficiency in adolescents", section on 'Iron supplements' and "Nutrition in pregnancy", section on 'Iron' and "Overview of dietary trace minerals", section on 'Iron'.)
Diagnostic issues — Successful overall management of the patient with iron deficiency anemia requires an attempt to identify and treat the underlying cause(s) of the iron deficiency (eg, blood loss from a tumor, varicosity, or other bleeding lesion; iron malabsorption). (See "Causes and diagnosis of iron deficiency anemia in the adult".)
Treatment issues — The choice of iron preparation depends upon the acuity of illness, as well as the ability of the patient to tolerate oral iron preparations. (See 'General principles' below.)
●Oral iron therapy – Because oral iron is inexpensive and effective when taken as prescribed, it is considered front line therapy. There are numerous conditions, however, for which oral iron is either poorly tolerated or ineffective. As examples:
•Gastrointestinal side effects are extremely common and may result in poor adherence to therapy. It is estimated that more than 70 percent of some populations to whom oral iron is prescribed do not take it .
•Various malabsorptive states (eg, celiac disease, Whipple's disease, bacterial overgrowth syndromes) may be associated with an inability to absorb iron optimally. (See 'Failure to respond to oral iron therapy' below and "Regulation of iron balance", section on 'Intestinal iron absorption'.)
•Treatment with oral iron may take as long as six to eight weeks in order to fully ameliorate the anemia, and as long as six months in order to replete iron stores.
•In patients with inflammatory bowel disease, the use of oral iron has been associated with worsening of the underlying disease, and may be poorly tolerated and ineffective . (See "Nutrient deficiencies in inflammatory bowel disease", section on 'Iron'.)
•In conditions such as heavy uterine bleeding, hereditary hemorrhagic telangiectasia, gastric bypass, or other causes of heavy blood loss, absorption of oral iron, even in maximal doses, may be unable to keep up with blood loss.
•Dialysis patients, especially those being treated with erythropoiesis-stimulating agents (ESAs), are unable to fully utilize iron administered orally. (See "Use of iron preparations in hemodialysis patients", section on 'Oral versus parenteral therapy'.)
•Non-dialysis chronic kidney disease patients have a number of reasons for their inability to absorb oral iron (eg, impaired iron transport, concomitant use of calcium-containing salts, H2 blockers, phosphate binders, generalized malabsorption). (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients", section on 'Indications for oral versus intravenous iron therapy'.)
•Oral iron, unlike the intravenous preparations, does not synergize well with ESAs (eg, erythropoietin, darbepoetin) in anemic cancer patients both on and off chemotherapy [5,6]. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Iron monitoring and supplementation'.)
•Inflammation-mediated induction of hepcidin, which regulates iron homeostasis, may result in suboptimal gastrointestinal absorption of orally administered iron in iron deficient subjects . Non-response to oral iron therapy does not rule out iron deficiency in such subjects, since two-thirds of the non-responders to oral iron in one study responded to treatment with intravenous iron (ferric carboxymaltose) . (See "Anemia of chronic disease (anemia of [chronic] inflammation)", section on 'Supplemental iron'.)
•Over a quarter of the world's population remains anemic; about half of this burden is due to iron deficiency anemia (IDA). Strategies to control IDA include daily and intermittent iron supplementation, home fortification with micronutrient powders, fortification of staple foods and condiments, and activities to improve food security and dietary diversity . The safety of routine iron supplementation in settings where infectious diseases such as malaria are endemic remains uncertain.
●Parenteral iron – Clinicians' historical reluctance to use parenteral iron preparations more widely can be traced, at least in part, to severe side effects (eg, anaphylaxis, shock, death) associated with earlier parenteral iron preparations, such as high molecular weight iron dextran. However there are numerous settings in which the use of intravenous iron preparations may be preferable. As examples:
•With the advent of parenteral iron formulations with improved toxicity profiles, the early switch to intravenous iron should be considered in those intolerant to the use of oral iron preparations. (See 'Parenteral iron therapy' below.)
•It has been estimated that the maximum amount of elemental iron that can be absorbed with an oral iron preparation is 25 mg/day , whereas, depending upon the preparation used, up to 1000 mg of elemental iron can be administered following a single infusion of intravenous iron. (See 'Available preparations' below.)
•Intravenous iron is effective for those unresponsive to or intolerant of oral iron. Published evidence supports the consideration of intravenous iron as an early option for those with inflammatory bowel disease (IBD) . Intravenous iron is considered frontline therapy in Europe for iron deficiency anemia associated with IBD with or without oral iron intolerance or ineffectiveness . For patients with chemotherapy induced anemia, NCCN Guidelines state that intravenous iron is the preferred route when iron supplementation is indicated, and K/DOQI guidelines indicate its use for iron replacement in dialysis patients. These issues are discussed in greater detail elsewhere in UpToDate.
•Intravenous iron is required when the amount of iron lost through daily blood loss exceeds the capacity of the gastrointestinal tract to absorb oral iron preparations. (See 'Indications' below.)
•For those who have undergone gastric bypass surgery and/or subtotal gastric resection, the limited ability of the remaining stomach to provide acid to protect ferric iron from being converted to the insoluble ferric hydroxide, and for facilitating intestinal absorption of ferric as well as ferrous iron, makes intravenous iron an especially good choice. Some patients, especially those having undergone minimally invasive procedures, such as gastric banding, may tolerate oral iron. This is less likely in Roux-en-Y or biliopancreatic diversion procedures. However, it is important to remember that all gastric bypass patients have a host of other nutritional perturbations post-operatively, and intravenous iron may simplify care.
●Blood transfusion – Blood transfusion should be reserved for the patient who is hemodynamically unstable because of active bleeding and/or shows evidence for end-organ ischemia. (See 'Blood transfusion' below.)
ORAL IRON THERAPY
General principles — Oral iron provides an inexpensive and effective means of restoring iron balance in a patient with iron deficiency without complicating co-morbid conditions. Frequent gastrointestinal side effects range from mild to severe constipation (especially in pregnant women), diarrhea, metallic taste, and thick, green stool. There are a few simple principles governing the use of oral iron [9-11]:
●Iron is not absorbed in the stomach and is absorbed best from the distal duodenum and proximal jejunum, where the iron transport proteins (eg, duodenal iron transporter, divalent metal transport protein and the iron export protein to blood, ferroportin) are most strongly expressed. Accordingly, enteric coated or sustained release capsules, which release iron further down in the intestinal tract, or which may be excreted intact in the stool, are inefficient sources of iron. (See "Regulation of iron balance", section on 'Duodenal iron transporter' and "Regulation of iron balance", section on 'Ferroportin'.)
●Iron salts should not be given with food because phosphates, phytates, and tannates in food bind the iron and impair its absorption (table 1). A number of other factors can inhibit the absorption of iron salts, including antacids, H2 receptor blockers, proton pump inhibitors, calcium-containing foods and beverages, calcium supplements, certain antibiotics (eg, quinolones, tetracycline), and the ingestion of iron along with cereals, dietary fiber, tea, coffee, eggs, or milk. (See "Regulation of iron balance", section on 'Intestinal iron absorption'.)
●Iron should be given two hours before, or four hours after, ingestion of antacids.
●Iron is best absorbed as the ferrous (Fe++) salt in a mildly acidic medium. As a result, we usually add a 250 mg ascorbic acid tablet or a half-glass of orange juice at the time of iron administration to enhance the degree of iron absorption.
●The iron preparation used should be based upon cost and effectiveness with minimal side effects. The least expensive preparation is ferrous sulfate; each tablet contains 325 mg of iron salts, of which 65 mg is elemental iron .
●Gastrointestinal tract symptoms (eg, abdominal discomfort, nausea/vomiting, diarrhea/constipation) suffered by some patients seem to be directly related to the amount of elemental iron ingested . Thus, the reported low incidence of side effects for some preparations can be explained by their low elemental iron content. As examples, one tablet of iron bis-glycinate (Ferrochel, Gentle Iron) contains 27 mg of elemental iron, while a 325 mg tablet of ferrous gluconate contains 36 mg of elemental iron. Both of these preparations contain significantly less elemental iron than a 325 mg tablet of ferrous sulfate (65 mg).
●Patients with persistent gastric intolerance to oral iron tablets may tolerate ferrous sulfate elixir, which provides 44 mg of elemental iron per 5 mL. Patients can titrate the dose up or down to the level at which the gastrointestinal symptoms become acceptable.
Choice of preparation — The most appropriate oral iron therapy is use of a tablet containing ferrous salts, such as:
●Ferrous fumarate – 106 mg elemental iron/tablet
●Ferrous sulfate – 65 mg elemental iron/tablet
●Ferrous gluconate – 28 to 36 mg iron/tablet
The recommended oral daily dose for the treatment of iron deficiency in adults is in the range of 150 to 200 mg/day of elemental iron. As an example, a single 325 mg ferrous sulfate tablet taken orally three times daily between meals provides an oral dose of 195 mg of elemental iron per day. There is no evidence that one of the above iron preparations is more effective than another for this purpose.
A large number of other oral iron-containing preparations and nutritional supplements are available, including the heme iron polypeptide Proferrin. They are generally more expensive than those described above and may not have been subjected to randomized clinical trials in patients with iron deficiency. Some (eg, enteric coated, sustained release preparations) may be both more expensive and poorly absorbed. Accordingly, we do not recommend their use.
Dosing in older adults — Appropriate dosing of iron for older adults with iron deficiency anemia is unclear. In a randomized study in 90 iron deficient hospitalized patients >80 years of age, daily doses of 15, 50, or 150 mg of elemental iron for two months were equally effective in raising hemoglobin and ferritin concentrations, while adverse side effects were significantly more common at the higher iron doses .
In our practice we treat iron deficiency in older adults by using 10 mL of iron sulfate elixir once daily (elemental iron content 88 mg) mixed in one-fifth of a glass of orange juice and taken 30 minutes before breakfast. The dose of elixir can be reduced to 5 mL if the 10 mL dose causes irritation. Similarly, a 50 or 100 mg tablet of ascorbic acid can be substituted for the orange juice.
Given the high prevalence of co-morbidities in older adult patients, chronic kidney disease and functional iron deficiency, we and others have found that the administration of intravenous iron offers an effective treatment option for those not tolerating, or not responding to treatment with, oral iron .
Expected response — An effective regimen for the treatment of uncomplicated iron deficiency with oral iron preparations should lead to the following responses:
●If pagophagia (pica for ice) is present, it often disappears almost as soon as oral or intravenous iron therapy is begun, well before there are any observable hematologic changes such as reticulocyte response. (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Pica and pagophagia'.)
●The patient will note an improved feeling of well-being within the first few days of treatment.
●In patients with moderate to severe anemia, a modest reticulocytosis will be seen, maximal in approximately 7 to 10 days. Patients with mild anemia may have little or no reticulocytosis.
●The hemoglobin concentration will rise slowly, usually beginning after approximately one to two weeks of treatment, and will rise approximately 2 g/dL over the ensuing three weeks. The hemoglobin deficit should be halved by approximately one month, and the hemoglobin level should return to normal by six to eight weeks.
●Typically, papillation of the tongue is decreased in patients with iron deficiency and can be used as a gauge of duration of symptoms. Classically, loss of papillae begins at the tip and lateral borders, and moves posteriorly and centrally. Following iron repletion, a rapid correction (weeks to months) is observed.
Side effects — Estimates are that 70 percent or more of patients complain of nausea, constipation, diarrhea, epigastric distress and/or vomiting after taking various oral iron preparations [3,15]. There are a number of treatment options for such patients:
●The patient may take an iron preparation containing a smaller dose of elemental iron (eg, switching from ferrous sulfate to ferrous gluconate), or may switch from a tablet to a liquid preparation, the dose of which (44 mg elemental iron per 5 mL) can be easily titrated by the patient (see 'General principles' above).
●The patient may slowly increase the dose from one tablet per day to the recommended three times per day, as tolerated.
●The iron may be taken with meals, although this will decrease absorption somewhat.
However, with the advent of parenteral iron formulations with more favorable toxicity profiles, the early use of intravenous iron should be considered in those intolerant to the use of oral iron preparations (see 'Parenteral iron therapy' below).
Duration of treatment — There is disagreement as to how long to continue oral iron therapy:
●Some physicians stop treatment with iron when the hemoglobin level becomes normal, so that further blood loss will cause anemia and alert the patient and physician to the return of the problem which caused the iron deficiency in the first place.
●Others believe that it is wise to treat for at least six months after the hemoglobin has normalized, in order to replenish iron stores.
Therefore, it is prudent to individualize the duration of iron replacement. As an example, it makes sense to fully replenish iron stores in a patient who became iron deficient as a consequence of multiple pregnancies. On the other hand, we stop therapy once the hemoglobin concentration is normalized in a patient who has occult gastrointestinal bleeding. In this latter setting, the return of iron deficiency is an important clue that bleeding has recurred.
Failure to respond to oral iron therapy — On occasion, a patient may not respond to oral iron therapy. The potential causes for this situation include the following (table 2) . (See "Regulation of iron balance", section on 'Iron-refractory iron deficiency anemia'.)
●Incorrect diagnosis (eg, thalassemia, myelodysplastic syndrome)
●Patient is non-adherent
●Presence of a coexisting disease or treatment interfering with response (eg, elevated hepcidin levels , renal failure, treatment with erythropoietin and/or cancer chemotherapy). Failure of response to oral iron therapy in these settings does not rule out the presence of iron deficiency, as some will respond to treatment with intravenous iron. (See 'Indications' below.)
●Medication is not being absorbed for physical reasons (eg, enteric coated tablets, concomitant use of antacids)
●Iron (blood) loss or need is in excess of the amount of iron able to be ingested (eg, severe continuous GI bleeding, dialysis patient, idiopathic pulmonary hemosiderosis). (See "Idiopathic pulmonary hemosiderosis" and "Hereditary hemorrhagic telangiectasia (Osler-Weber-Rendu syndrome)".)
●There is acquired malabsorption for iron. In one study, for example, refractoriness to oral iron treatment was noted in all patients with celiac disease and approximately 70 percent of those with autoimmune atrophic gastritis or Helicobacter pylori infection . (See "Pathogenesis, epidemiology, and clinical manifestations of celiac disease in adults", section on 'Iron deficiency' and "Metaplastic (chronic) atrophic gastritis", section on 'Helicobacter pylori' and "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Oral iron absorption test'.)
●There is an inherited condition associated with iron deficiency anemia and a failure to respond to treatment with oral iron (eg, iron-resistant iron deficiency anemia, IRIDA). This condition is discussed in depth separately. (See "Regulation of iron balance", section on 'Iron-refractory iron deficiency anemia'.)
The appropriate treatment depends upon the cause for failure to respond. In selected cases, treatment of the underlying cause is preferred. Examples include :
●Celiac disease – Initiation of gluten-free diet (see "Management of celiac disease in adults")
●Helicobacter pylori infection (see "Treatment regimens for Helicobacter pylori")
●Malabsorption of oral iron – Use of intravenous iron preparations (see 'Indications' below)
Pregnancy — Standard treatment of iron deficiency in pregnancy is the same as that in nonpregnant, postpartum, premenopausal, and postmenopausal women. However, in the pregnant patient, bloating and constipation are common problems due to high progesterone levels, which slow bowel movement, as well as the increasing pressure of the gravid uterus on the rectum. (See "Maternal gastrointestinal tract adaptation to pregnancy", section on 'Bloating and constipation'.)
Such side effects can be exacerbated by treatment with oral iron, and can be partially managed by reducing the amount of iron given and/or modifying the patient's diet, both of which require patient adherence. Furthermore, up to 70 percent of pregnant women to whom oral iron is prescribed report adverse events . While numerous publications have shown the safety and efficacy of parenteral iron in this setting [19-28], its use in pregnancy is sporadic at best and is hindered by the fact that no parenteral iron preparation has been given a US Food and Drug Administration (FDA) category "A" rating for use in pregnancy (table 3).
Nevertheless, a number of observations suggest the safety of intravenous iron in pregnant women:
●In our practice, we routinely administer 1000 mg of low molecular weight iron dextran in one hour to iron deficient pregnant women whether or not they are oral iron intolerant . Although this agent has an FDA category "C" rating in pregnancy (table 3), in over 1000 treated subjects, no serious adverse effects have been observed.
Given the preponderance of published evidence on the safety of intravenous iron in the pregnant patient, we believe that the failure to use intravenous iron in this population appears to represent an unmet clinical need. From the standpoint of the developing fetus, a more liberal use of IV iron in pregnancy will likely minimize the chance that the neonate of an iron deficient woman will also be iron deficient, especially in view of evidence that iron deficient neonates not only have delayed growth and development, but also an increase in behavioral problems later in childhood .
PARENTERAL IRON THERAPY
Indications — There are a number of indications for the use of parenteral, rather than oral, iron preparations. These are discussed below. Given the safety and efficacy of IV iron in a broad spectrum of diseases associated with iron deficiency, the current paradigm that oral iron is first line therapy should be reconsidered.
Excessive continuing blood loss — Currently, parenteral iron is most often used in iron deficient patients whose
level of continued bleeding, usually gastrointestinal or menstrual, exceeds the ability of the gastrointestinal tract to absorb iron. As an example, in one study the maximum amount of iron capable of being absorbed from oral iron preparations was found to be 25 mg/day , the amount of iron in 25 mL of packed red cells or approximately 60 mL of whole blood. Accordingly, oral iron therapy alone would not expected to be able to keep up with chronic blood loss averaging ≥25 mL/day of packed red cells or a transfusion requirement of one unit of packed red cells every 8 to 10 days.
Inflammatory bowel disease — Many patients with inflammatory bowel disease (IBD) and iron deficiency have severe intolerance to oral iron preparations, which may also worsen IBD disease activity. (See "Nutrient deficiencies in inflammatory bowel disease", section on 'Iron'.)
Further, unlike oral iron, IV iron is able to partially overcome the iron restricted erythropoiesis associated with inflammation. Numerous studies in the United States and other countries have demonstrated the safety and efficacy of iron sucrose, LMW iron dextran, ferumoxytol, and ferric carboxymaltose in patients with inflammatory bowel disease [4,31,32]. (See 'Treatment issues' above.)
It has therefore been suggested that intravenous, rather than oral, iron should be considered in patients with IBD for the following scenarios :
●Anemia and unresponsiveness to or intolerance of oral iron
●Need for a quick recovery from anemia
●Adjuvant use of erythropoietin
Chronic kidney disease — IV iron is the current standard in both dialysis and non-dialysis associated chronic kidney disease patients for multiple reasons, including ongoing blood loss associated with the procedure, the need for adequate iron to respond to the administration of erythropoietic stimulating agents, as well as the frequent inability of these patients to utilize iron administered orally [34,35]. (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients", section on 'Indications for oral versus intravenous iron therapy'.)
Use in cancer patients — A large number of prospective studies support the observation that IV iron, unlike oral iron, synergizes with erythropoiesis-stimulating agents (eg, erythropoietin, darbepoetin) therapy in anemic cancer patients both on and off chemotherapy . This subject is discussed in detail separately. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Iron monitoring and supplementation'.)
There is limited information on the efficacy of IV iron in anemic cancer patients receiving chemotherapy in the absence of treatment with erythropoiesis-stimulating agents [6,36,37]. An observational study in anemic cancer patients receiving IV iron (ferric carboxymaltose, median dose 1000 mg of elemental iron) indicated that patients with baseline hemoglobin levels up to 11.0 g/dL and serum ferritin levels up to 500 ng/mL responded to treatment with an increase in hemoglobin and a reduction in the need for red cell transfusions . Benefit was also noted for those with ferritin levels >500 ng/mL if transferrin saturation was <20 percent (mean baseline saturation 14 percent). IV iron was well tolerated, with adverse drug reactions, mainly nausea and diarrhea, reported in 2.3 percent.
Use in heart failure — Anemia is a frequent finding in patients with heart failure (HF) and can worsen cardiac function and enhance symptoms. While available evidence suggests that IV iron provides symptomatic benefit in selected patients with HF, the long-term effects of such treatment are not known. The use of IV iron, red cell transfusion, and erythropoiesis-stimulating agents in patients with heart failure is discussed in depth separately. (See "Approach to anemia in adults with heart failure", section on 'Treatment'.)
Available preparations — There are a number of parenteral iron formulations approved for use in various countries throughout the world. The table lists most of these, along with their maximum approved doses, ability to perform total-dose infusion, as well as their need for premedication and/or a test dose (table 4). Specific details concerning each are outlined below.
Iron dextran — Iron dextran preparations contain 50 mg of elemental iron/mL. Although iron dextran can be given either by the intramuscular (IM) or intravenous (IV) route, we recommend that it only be given by the IV route, for reasons discussed below. (See 'Intramuscular iron' below.)
Both local and systemic side effects can occur following use of iron dextran, with an anticipated frequency of reactions of 4.7 percent in one older study . High molecular weight (HMW) iron dextran preparations (Dexferrum) are associated with a considerably higher incidence of adverse events than are the low molecular weight (LMW) preparations (INFeD, Cosmofer) [35,40,41]. Minor, self-limiting infusion reactions occur in less 1 percent. Importantly, when HMW preparations are avoided, serious adverse events from iron dextran are extremely rare (<1:200,000). (See 'Prevention and treatment of adverse drug events' below.)
The National Comprehensive Cancer Network (NCCN) and the nursing association of the American Society of Nephrology have proscribed the use of HMW iron dextran by brand (Dexferrum); this product has been removed from the formularies of the United States Veterans Administration Medical Centers.
Total dose infusion — LMW iron dextran may be given as a total dose infusion (TDI). However, in that there is no evidence that doses larger than 1000 mg are clinically useful, it has been our policy to routinely administer 1000 mg over one hour . (See 'Calculation of the dose' below.)
TDI of LMW iron dextran has been shown to be safe and effective in pregnancy, the peripartum period, heavy uterine bleeding, inflammatory bowel disease, gastric bypass, hereditary hemorrhagic telangiectasias, chronic kidney disease, and the restless legs syndrome [25,42,43].
Test dose — A test dose of 25 mg given by slow IV push over five minutes is required when giving this agent for the first time. After a 15-minute observation period, the remainder of the dose may be infused. Subsequent dose(s) may be administered by IV bolus at rate of ≤50 mg/minute or diluted in 250 to 1000 mL normal saline and infused over one to six hours. We routinely administer 1000 mg of LMW iron dextran in 250 mL of normal saline over one hour without premedication . The initial 25 mL should be given slowly and patient should be observed for allergic reactions.
In those with more than one drug allergy or asthma we premedicate with corticosteroids (125 mg methylprednisolone IV).
Ferric gluconate complex — Ferric gluconate complex (Ferrlecit) is only approved for IV use. Data from Europe and the United States indicate that, compared with iron dextran, sodium ferric gluconate complex in sucrose has a reduced incidence of adverse allergic reactions (3.3 versus 8.7 allergic events per one million doses per year) . In prospective and intra-institutional retrospective studies, no difference in adverse event rates with either iron salt (ferric gluconate and iron sucrose) was observed .
One group has reported on the efficacy and safety of 125 mg of ferric gluconate complex given either undiluted by slow IV push at a rate of 12.5 mg/minute or diluted in 100 mL isotonic saline and infused over 30 to 60 minutes, in 74 patients with iron deficiency anemia and normal levels of serum creatinine . Of 639 infusions, 11 reactions (1.7 percent) were documented; no reaction was considered severe or anaphylactic. Two reactions were moderately severe (eg, dyspnea, severe urticaria, neck and back spasm), causing the infusion to be stopped. All other reactions were minor (eg, pruritus, palpitations, dizziness), causing the infusion to be temporarily stopped, following which all patients were able to continue the infusion. When measured in 56 of the 74 patients, all efficacy end points (eg, increases in hemoglobin, hematocrit, mean corpuscular volume, serum ferritin) showed significant improvement. (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients" and "Use of iron preparations in hemodialysis patients".)
When ferric gluconate complex is used for this purpose, up to 187.5 mg is administered (15 mL) at any one setting. It may be diluted and infused over 20 to 30 minutes. It can also be administered as a 125 mg two-minute bolus in dialysis patients. Although rarely done, 250 mg infusions over one hour have been reported to be well tolerated . Larger single doses should not be attempted. The remainder of the calculated dose of iron is given at subsequent treatment sessions at this rate . (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients", section on 'Indications for oral versus intravenous iron therapy'.)
Test dose — Product labeling for ferric gluconate does not indicate the need for a test dose, however in patients with a sensitivity to iron dextran or with other drug allergies a test dose is recommended.
Iron sucrose — Iron sucrose (Venofer, iron saccharate, 20 mg iron/mL) is only approved for IV use. The safety and efficacy profile of iron sucrose is similar to that of ferric gluconate. Iron sucrose has been shown to be safe and efficacious in dialysis, non-dialysis CKD, inflammatory bowel disease, chemotherapy-induced anemia, the peripartum period, gastric bypass, heavy uterine bleeding, and a host of other conditions associated with iron lack. (See "Iron balance in non-dialysis, peritoneal dialysis, and home hemodialysis patients" and "Use of iron preparations in hemodialysis patients".)
The recommended dose for anemic cancer patients receiving erythropoiesis-stimulating agents is 200 mg infused over 60 minutes, repeated every two to three weeks. It is routinely given as a 200 mg IV bolus over two minutes in dialysis centers. While approved as a 500 mg infusion over longer periods of time (hours), single doses greater than 300 mg are not recommended. (See "Role of erythropoiesis-stimulating agents in the treatment of anemia in patients with cancer", section on 'Iron monitoring and supplementation'.)
Test dose — Product labeling for iron sucrose does not indicate the need for a test dose in product-naive patients, but a test dose is recommended (25 mg by slow IV push) in patients who are sensitive to iron dextran or have other drug allergies.
Ferumoxytol — Ferumoxytol (Feraheme) is composed of superparamagnetic iron oxide nanoparticles coated with a low molecular weight semisynthetic carbohydrate. It has been deemed safe and effective when given as a rapid intravenous infusion of up to 510 mg of elemental iron in a volume of 17 mL (infusion rate: up to 1 mL/second) in patients with chronic kidney disease (CKD) and those on dialysis . (See "Use of iron preparations in hemodialysis patients", section on 'Ferumoxytol'.)
However, based on both in vitro data and in vivo experience, we strongly recommend that ferumoxytol not be infused in less than one minute [50,51], since the few cases of anaphylactic reaction that have been reported have all been associated with bolus infusions over periods between 17 and 60 seconds [52,53]. While ferumoxytol has been shown to be safe and efficacious as a 1020 mg infusion over 15 minutes with no episodes of anaphylaxis , ferumoxytol is only approved at this time for a 510 mg injection in patients with CKD.
The US Food and Drug Administration (FDA) has approved ferumoxytol for the treatment of iron deficiency anemia in adult patients with chronic kidney disease. The most important safety concerns were hypotension and/or hypersensitivity reactions, including anaphylaxis and/or anaphylactoid reactions. Ferumoxytol administration may transiently affect the diagnostic ability of magnetic resonance imaging. If an MRI is ordered within four weeks of a ferumoxytol injection, the radiologist should be notified.
Results are available from a randomized, double-blind safety and efficacy trial of intravenous ferumoxytol (n = 609, 510 mg administered in under one minute and repeated two to eight days later) versus intravenous placebo (n = 203, administered in the same fashion) in adults with iron deficiency anemia previously unresponsive to, or unable to tolerate, oral iron. Results included the following :
●The primary efficacy outcome, the proportion of patients achieving a hemoglobin increase of ≥2 g/dL at week 5, was met in 81.1 versus 5.5 percent of those treated with ferumoxytol or placebo, respectively.
●The proportion of patients achieving a hemoglobin level ≥12 g/dL at any time from baseline to five weeks was 50.5 and 3.0 percent in those treated with ferumoxytol or placebo, respectively.
●The incidence of serious adverse events did not differ between the two treatment arms and was 2.6 versus 3.0 percent for the ferumoxytol and placebo groups, respectively. There was one anaphylactic reaction (0.2 percent) and three hypersensitivity reactions (0.5 percent) in those treated with ferumoxytol. All serious adverse events resolved without sequelae. Three deaths occurred more than 35 days post-treatment; none was considered to be related to the study drug.
A second randomized trial compared ferumoxytol with iron sucrose for the treatment of iron deficiency anemia in 605 adult patients with a history of unsatisfactory oral iron therapy or intolerance to oral iron. Ferumoxytol was given to 406 subjects as two injections of 510 mg administered over 30 to 60 seconds and repeated five days later, while iron sucrose was given as five infusions or injections of 200 mg on five non-consecutive days over a 14-day period. A test dose of a 20 mg injection or 25 mg infusion of iron sucrose was given to iron sucrose-naïve patients in compliance with labeling requirements of the countries in which this study was conducted. Results included the following :
●The proportion of patients achieving a hemoglobin increase of ≥2 g/dL at any time between baseline and five weeks, the primary efficacy endpoint, was 84 versus 81 percent for those receiving ferumoxytol or iron sucrose, respectively. The percent of subjects achieving a hemoglobin level ≥12 g/dL at any time from baseline to five weeks was significantly greater in those receiving ferumoxytol (67 versus 48 percent for those receiving iron sucrose).
●Quality-of-life measures and safety outcomes were similar between the two treatment groups. There were no drug-related deaths in either treatment arm. Two ferumoxytol-treated patients (0.5 percent) had serious adverse events deemed by the investigators to be related to the study drug (anaphylactic reaction in one patient and one event each of hypertension, angioedema, urticaria, and tachycardia in the other).
The efficacy and safety of ferumoxytol are further supported by a prospective, randomized study in 162 patients with chronic kidney disease (CKD) randomly assigned to receive either 1.02 grams of ferumoxytol administered as two 510 mg injections (administered by rapid IV bolus injection) or 10 IV doses of 100 mg of iron sucrose in those with CKD undergoing dialysis or 200 mg of IV iron sucrose in non-dialysis CKD. The rates of serious adverse events and related serious adverse events were similar between the two treatment arms. Based on an ANOVA model adjusted for baseline hemoglobin levels and dialysis status, no significant difference in efficacy and safety was observed between these two IV iron preparations .
Currently there are no published data on the safety and efficacy of ferumoxytol in pregnancy.
Ferric carboxymaltose — Ferric carboxymaltose (Ferinject, Injectafer) is a novel stable iron complex for intravenous use that can be given at single doses of up to 1000 mg of elemental iron per week over a recommended infusion time of 15 minutes. A number of trials have shown efficacy and safety of this agent in iron deficient patients in a number of different settings (eg, heavy uterine bleeding, postpartum women, chronic renal failure, inflammatory bowel disease, heart failure, nonresponse to oral iron) [7,56-62].
Ferric carboxymaltose was shown to be effective in alleviating symptoms of congestive heart failure  and was the first agent to demonstrate efficacy in chemotherapy-associated anemia when administered without concomitant use of an erythropoiesis-stimulating agent . This agent is licensed for use in Europe, Asia, and New Zealand, and is approved for use in the United States in patients with iron deficiency anemia and intolerance or unsatisfactory response to oral iron and for treatment of iron deficiency anemia in adults with nondialysis-dependent chronic kidney disease. (See "Approach to anemia in adults with heart failure", section on 'Intravenous iron'.)
The US Food and Drug Administration (FDA) had delayed approval of this agent due to hypophosphatemia observed at two weeks and an imbalance of cardiovascular events and deaths (none of which was attributed to the drug) in the treatment arm compared with controls. No clinical sequelae secondary to the hypophosphatemia associated with ferric carboxymaltose infusions have been reported.
While listed as Schedule C in pregnancy by the US FDA, this agent has been shown to be well tolerated in pregnancy in two published series, neither of which reported any serious adverse events (eg, allergic, hypotensive, or anaphylactic reactions) following its administration to 250 pregnant subjects [63,64]. Based on the preponderance of published evidence, ferric carboxymaltose is safe and effective, with a side effect profile similar to the other available intravenous iron formulations.
Iron isomaltoside — This formulation is available only in Europe. It can be safely administered as a 15-minute infusion at a dose of 20 mg/kg.
Intramuscular iron — Mobilization of iron from intramuscular (IM) sites is slow. As a result, the rise in the hemoglobin concentration following IM administration is only slightly faster than that which occurs following the use of oral iron preparations.
●Parenteral iron, when given by IM injection, is painful, stains the buttocks, has been associated with the development of gluteal sarcomas, and may be poorly absorbed [65,66].
●Patients who have very brisk continuing bleeding (as with gastrointestinal angiodysplasia) are difficult to treat with an IM regimen because repeated courses of IM iron are painful, and the utilization of iron given via this route is variable.
●Patients with severe malabsorption and/or malnutrition may not be candidates for IM treatment if they have a markedly reduced muscle mass into which the iron preparation can be injected.
For all of the above reasons, including the fact that IM administration of iron dextran has not been shown to be safer or less toxic than the intravenous (IV) route, the most appropriate parenteral route is the IV one .
Prevention and treatment of adverse drug events — The following sections should be required reading for all clinicians contemplating the use of an intravenous iron preparation.
Overview — Each of the available formulations of IV iron has been associated with reports of life-threatening adverse drug events (ADEs) [41,68,69]. While the US Food and Drug Administration's Adverse Event Reporting System (AERS) has been employed for comparing such rates [41,70], it is not possible to draw valid conclusions about comparative risks from the AERS database and other voluntarily submitted reports [68,71].
There exist only a small number of randomized, prospective trials comparing the relative safety of the various intravenous iron preparations : three have shown relatively equal safety for low molecular weight iron dextran and iron sucrose [69,73,74]; one has shown relatively equal safety for iron sucrose and ferric gluconate complex ; while one, in abstract form, has shown comparability of safety between iron sucrose and ferumoxytol . While the preponderance of published evidence indicates that low molecular iron dextran preparations are associated with fewer adverse reactions than high molecular weight iron dextran preparations , it is not otherwise possible at this time to conclude that any one intravenous iron preparation is safer than another [68,78].
Patients with a history of drug allergy or multiple drug allergies may be at increased risk of anaphylactic-type reactions. It is a US FDA recommendation that resuscitation equipment and personnel trained in the detection and treatment of anaphylactic-type reactions be readily available during administration of all iron dextran preparations . However, while we have seen such anaphylactic-type reactions to high molecular weight iron dextran, we have not seen such reactions after infusions of low molecular weight iron dextran preparations , ferumoxytol, iron sucrose, or ferric gluconate complex.
●Systemic effects of IV iron include self-limiting fever, arthralgias, and myalgias, usually within 24 hours of infusions. These resolve without therapy but a small clinical benefit is obtained from the use of nonsteroidal anti-inflammatory agents.
●A flare of arthritis in patients with inflammatory arthritis, such as rheumatoid arthritis, commonly occurs. This can usually be abated by the use of 125 mg of intravenous methylprednisolone immediately before the iron infusion and 1 mg/kg per day of oral prednisone for four days thereafter. The cause of these reactions is unknown as tryptase levels, a marker of mast cell degranulation, have been normal following these reactions. (See "Allergic reactions to vaccines", section on 'Dextran' and "Perioperative anaphylaxis: Evaluation and prevention of recurrent reactions", section on 'Colloids'.)
●Approximately 0.5 to 1 percent of patients may complain of arthralgias, myalgias, or flushing without associated hypotension, tachypnea, tachycardia, wheezing, stridor, or periorbital edema [67,78]. After symptoms abate, rechallenge is appropriate and symptoms rarely recur. The empiric use of steroids prior to rechallenge may be beneficial, but is untested. In the rare patient who reacts in this manner twice, the IV formulation should be changed. No intervention for these complaints is necessary. Specifically, the use of antihistamines for prevention or treatment is inappropriate. (See 'Need for premedication' below.)
Risk of infection — Bacteria and other infectious agents require iron as a growth factor, and patients with hereditary hemochromatosis and iron overload are known to be at increased risk for certain serious bacterial infections . These observations have suggested that the use of therapeutic doses of iron might be associated with an increased risk of infection. (See "Clinical manifestations of hereditary hemochromatosis", section on 'Susceptibility to specific infections'.)
However, we believe that the potential risk of infection following the use of iron in general and IV iron in particular has been overstated. As examples:
●A meta-analysis of this subject, which reported an increased risk of infection following the use of IV iron (when compared with oral iron, RR 1.33; 95% CI 1.10-1.64), acknowledged that information on the risk of infection was available in only 24 of the 72 studies included in their meta-analysis, suggesting that missing data could have created unmeasured bias and a false positive result. In addition, they could not uncover a dose-response association between iron and infectious risk, and rates of mortality and other serious events in patients randomly assigned to treatment with IV iron were not increased [81,82].
●When the risk of infection was specifically determined in large trials in hemodialysis patients , patients with iron deficiency anemia plus non-dialysis-dependent chronic kidney disease , those with heart failure , following cardiac  or orthopedic surgery , or in those with chemotherapy-induced anemia [86,87], the use of IV iron was not associated with an increased risk of infection. (See "Use of iron preparations in hemodialysis patients", section on 'Adverse effects other than anaphylaxis'.)
Accordingly, while IV iron should not be employed in patients with active infection , the preponderance of published evidence does not support the contention that the use of IV iron is associated with an increased risk of infection.
Need for premedication — The reluctance to use intravenous iron is at least in part due to misunderstanding and misinterpretation of the clinical nature of adverse events with IV iron . As an example, myalgias, when they include chest and back discomfort, are mistakenly described as anaphylaxis, prompting unnecessary interventions with antihistamines and pressors . Accordingly, we employ the following guidelines in patients about to receive intravenous iron preparations:
●There is published evidence suggesting that the majority of reactions attributed to IV iron are actually due to premedication with antihistamines, particularly diphenhydramine . Such use of antihistamines can cause hypotension, somnolence, flushing, and supraventricular tachycardia, prompting inappropriate intervention with pressor agents and the conversion of a minor reaction to a severe one. Accordingly, the use of antihistamines for prevention or treatment of these reactions is inappropriate.
●Those with asthma or more than one drug allergy are more likely to experience a minor infusion reaction. We routinely premedicate these patients with 125 mg of intravenous methylprednisolone. This recommendation applies to all of the intravenous iron formulations.
●In the absence of a history of asthma or more than one drug allergy, we strongly recommend that premedication not be given.
When the above tenets are followed and the use of high molecular weight iron dextran is avoided, serious adverse events with IV iron are extremely rare, with an estimated frequency of less than 1:200,000 .
Calculation of the dose — In selecting the dose of parenteral iron required, one calculates the iron deficit based upon the fact that 1 g of hemoglobin contains 3.3 mg of elemental iron (table 5), along with other assumptions concerning blood volume, desired hemoglobin level, and whether or not one wishes to provide additional iron for body stores [92,93] (See 'Iron dextran' above.)
Correction of anemia — Assume, for example, that a 60 kg woman with a hemoglobin concentration of 8 g/dL due to iron deficiency needs parenteral iron replacement, which will be given intravenously in the form of iron sucrose (20 mg iron/mL).
●The normal blood volume is approximately 65 mL/kg. Thus, her total blood volume is approximately 3900 mL or 39 deciliters (65 mL/kg x 60 kg).
●A normal hemoglobin concentration would be 14 g/dL. Thus, her hemoglobin deficit is 6 g/dL with a total deficit of 234 g (6 g/dL x 39 dL).
●Each gram of hemoglobin contains 3.3 mg of iron. Thus, her total red cell iron deficit is 772 mg (234 g of hemoglobin x 3.3 mg Fe per gram of hemoglobin). This calculation does not factor in additional iron for deposition into stores (see below).
●At an iron concentration of 20 mg/mL, this would require a total of 38.6 mL of iron sucrose.
●In preparing to infuse this or any other amount of iron sucrose, the product information sheet, as well as institutional guidelines, should be consulted for the need for a test dose, proper dilution, rate of infusion, and maximal allowable dose per infusion. In the case of iron sucrose, the maximum approved dose is 200 to 300 mg of elemental iron (table 4), which would require more than two separate infusions to repair this patient's iron deficit.
However, in that there is no evidence that doses larger than 1000 mg are clinically useful, it has been our policy to routinely administer a fixed 1000 mg dose over one hour to iron deficient patients receiving intravenous low molecular weight iron dextran . In the above example, infusion of 1000 mg of elemental iron would repair this patient's iron deficit of 772 mg and supply an additional 228 mg of iron (3.8 mg/kg) to her iron stores.
Repletion of iron stores — The issue of whether to replete iron stores in the patient with iron deficiency anemia is discussed above. Iron stores in most normal men and women are in the range of 10 and 5 mg/kg, respectively. (See 'Duration of treatment' above and "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Normal body iron content'.)
BLOOD TRANSFUSION — For the patient who is hemodynamically unstable because of active bleeding, and/or who shows evidence for end-organ ischemia secondary to severe iron deficiency anemia, packed red blood cell transfusion can be life saving. Each unit of packed cells with a volume of 300 mL contains approximately 200 mL of red cells and 200 mg of iron in the form of hemoglobin heme. Transfusion of one such unit to an adult will raise the hematocrit by roughly 3 percentage points (and the hemoglobin by approximately 1 g/dL) unless there is continued bleeding.
While blood transfusion therapy should be individualized, transfusion is not recommended in hemodynamically stable patients without end-organ ischemia. This subject is discussed in depth separately. (See "Indications and hemoglobin thresholds for red blood cell transfusion in the adult", section on 'Society guidelines'.)
TREATMENT OF FATIGUE IN NONANEMIC SUBJECTS — A randomized, double-blind study evaluated the efficacy and safety of intravenous iron (cumulative dose: 800 mg of iron as iron (III)-hydroxide sucrose given in four infusions over a two-week period) versus placebo (0.9 percent saline) for the treatment of fatigue in 90 nonanemic (hemoglobin ≥12.0 g/dL) premenopausal women with serum ferritin levels ≤50 ng/mL. Results included :
●Significant improvement in the fatigue score at six weeks, as evaluated by the Brief Fatigue Inventory questionnaire, was noted only in the subgroup of women with serum ferritins ≤15 ng/mL (82 percent with intravenous iron versus 47 percent of those treated with placebo).
●Treatment with intravenous iron significantly increased serum ferritin levels and transferrin saturation, but did not increase hemoglobin values. Drug-associated adverse events were observed in 21 percent of those treated with intravenous iron versus 7 percent in the placebo-treated group; none of these events was serious.
The iron in the above-noted study was given intravenously. However, other studies have shown that iron given orally can also improve fatigue in similar patients [94-97], can improve exercise capacity in nonanemic adolescent runners with serum ferritin levels <20 ng/mL , and can improve symptoms of fatigue in nonanemic female blood donors with serum ferritins <10 ng/mL .
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient information: Anemia caused by low iron (The Basics)")
●Beyond the Basics topics (see "Patient information: Anemia caused by low iron (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
Indications for treatment — While some patients with iron deficiency anemia will be asymptomatic, most will have symptoms. In any case, all should receive treatment. (See 'Management overview' above.)
Importantly, the cause for the iron deficiency should be sought in every patient, as the iron deficiency may be secondary to a treatable condition (eg, colonic malignancy) and/or may make the patient liable for recurrence of the iron deficient state (eg, bleeding gastrointestinal telangiectasias in hereditary hemorrhagic telangiectasia). (See "Causes and diagnosis of iron deficiency anemia in the adult", section on 'Search for source of blood and iron loss'.)
●Because of ease of treatment, we recommend that patients with uncomplicated iron deficiency anemia be treated with oral iron rather than an intravenous (IV) iron formulation (Grade 1B).
An appropriate daily dose for the treatment of iron deficiency in adults is in the range of 150 to 200 mg/day of elemental iron. While there is insufficient information to select one oral iron preparation over another, one 325 mg tablet of ferrous sulfate (iron content 65 mg) taken three times per day contains this amount of iron. (See 'Oral iron therapy' above.)
●For patients who have a history of intolerance to oral iron therapy, published evidence supports a larger and earlier role for intravenous iron. Intramuscular iron preparations should not be used for this purpose. (See 'General principles' above and 'Intramuscular iron' above.)
•High molecular weight iron dextran preparations are associated with a considerably higher incidence of adverse events than are the low molecular weight preparations, and should not be employed. Otherwise, there is insufficient evidence for the superiority of one parenteral iron preparation over another (ie, iron sucrose, ferric gluconate complex, low molecular weight iron dextran, ferumoxytol) (table 4). (See 'Available preparations' above and 'Prevention and treatment of adverse drug events' above.)
•Clinicians contemplating the use of intravenous iron preparations should be fully conversant with requirements for a test dose, rates of infusion, maximum allowed doses, and the need, if any, for premedication. The use of antihistamines for premedication or treatment of infusional side effects is to be avoided. (See 'Prevention and treatment of adverse drug events' above.)
The choice of the length of treatment with iron depends upon whether the treatment goal is to restore hemoglobin levels to normal or to restore both hemoglobin levels and iron stores to normal. (See 'Duration of treatment' above.)
Resistant or relapsed disease
●For patients who have failed to respond to oral or parenteral iron therapy, the cause for this failure should be determined and appropriate action undertaken. The table outlines the various steps that should be taken when this occurs (table 2). (See 'Failure to respond to oral iron therapy' above.)
●Relapsed disease (ie, recurrence of iron deficiency following successful treatment) is most often due to persistence or relapse of the initial inciting cause (eg, recurrent gastrointestinal or uterine bleeding), and should be treated appropriately.
All topics are updated as new information becomes available. Our peer review process typically takes one to six weeks depending on the issue.