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Mechanism of Action
US Drug Names
Elemental Iron Content:
NOTE: Different iron formulations are not directly exchangeable on a mg per mg basis; the different salts contain roughly the following amounts of elemental iron:
Iron Formulation-(% elemental iron)
Ferrochel (ferrous bis-glycinate chelate): 75% elemental iron
Ferrous sulfate-(20% elemental iron)
Ferrous sulfate, exsiccated (dried)-(30% elemental iron)
Ferrous gluconate- (12% elemental iron)
Ferrous fumarate-(33% elemental iron)
Carbonyl iron -(100% elemental iron)
Polysaccharide-iron complex- (100% elemental iron) (see Polysaccharide-iron complex monograph).
NOTE: All dosages are expressed in terms of elemental iron. These RDAs were revised by the IOM Food and Nutrition Board in 2001.
15 mg PO once daily in the first trimester; 27 mg PO once daily during the last 2 trimesters.
9 to 10 mg PO once daily.
8 mg PO once daily.
18 mg PO once daily.
11 mg PO once daily.
15 mg PO once daily.
10 mg PO once daily.
7 mg PO once daily.
RDA is not established. An adequate intake is 0.27 mg per day PO and is based on the average iron intake of breast-fed infants.
2 mg elemental iron/kg/day PO. Up to 4 mg elemental iron/kg/day PO may be required for premature infants weighing less than 1,500 g at birth. Do not exceed 15 mg/day PO of elemental iron.
60 mg elemental iron PO 1 to 3 times daily for 4 weeks  . Repeat anemia screening. An increase in hemoglobin of 1 g/dL or more or an increase in hematocrit of 3% or more confirms the diagnosis of iron deficiency anemia. If iron deficiency anemia is confirmed, continue iron treatment for another 2 to 3 months, then repeat anemia screening. Repeat anemia screening again 6 months after successful treatment is completed. Smaller dosages may be used if GI intolerance occurs; however, correction of the deficiency will occur at a slower rate.
3 to 6 mg elemental iron/kg/day PO in 1 to 3 divided doses for 4 weeks. In school-aged children, a dose of 60 mg elemental iron/day has also been recommended. Repeat anemia screening. An increase in hemoglobin of 1 g/dL or more or an increase in hematocrit of 3% or more confirms the diagnosis of iron-deficiency anemia. If iron deficiency anemia is confirmed, continue iron treatment for another 2 to 3 months, then repeat anemia screening. Repeat anemia screening again 6 months after successful treatment is completed. 
3 to 6 mg elemental iron/kg/day PO in 1 to 3 divided doses for 4 weeks. Repeat anemia screening. An increase in hemoglobin of 1 g/dL or more or an increase in hematocrit of 3% or more confirms the diagnosis of iron-deficiency anemia. If iron deficiency anemia is confirmed, continue iron treatment for another 2 to 3 months then repeat anemia screening. Repeat anemia screening again 6 months after successful treatment is completed. 
Usual initial dose is 2 to 4 mg elemental iron/kg/day PO. If erythropoietin alfa is used, doses up to 6 mg elemental iron/kg/day is needed as active erythropoiesis requires additional iron. Begin supplementation between age 2 and 8 weeks and continue for 12 months; starting supplementation at 2 weeks of life may reduce the risk of anemia between age 2 and 6 months. Preterm infants on iron-fortified specialized formula for preterm infants do not require additional iron supplementation.  NOTE: Prior to administering iron drops, verify the concentration on the bottle; multiple concentrations are available.
3 to 6 mg elemental iron/kg/day PO for 3 months. If erythropoietin alfa is used, up to 6 mg elemental iron/kg/day is needed as active erythropoiesis requires additional iron. NOTE: Prior to administering iron drops, verify the concentration on the bottle; multiple concentrations are available.
Patients with hepatic disease should receive iron supplementation with caution and only under the direction of a health care prescriber. The liver is one of the main storage sites for iron, and some patients with chronic liver disease may have excessive iron storage. Specific guidelines for dosage adjustments in hepatic impairment are not available.
Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.
Before supplementing hemodialysis patients with iron, a diagnosis of absolute or functional iron deficiency should be made. Follow normal recommended doses; it appears that no dosage adjustments are needed. Iron supplements are not hemodialyzable.
Iron salts are used in the treatment and prevention of iron-deficiency anemia and for nutritional supplementation when iron intake in the diet is inadequate to meet body needs. Iron is an essential mineral and is a component of hemoglobin, myoglobin, and multiple enzymes. The anemia of iron deficiency may result in fatigue, exertional shortness of breath, tachycardia, pallor, headache, glossitis, koilonychia (spoon nails), and decreased cognitive functioning. Meat, fish, and poultry are excellent sources of iron in the diet. Other good dietary sources of iron include beans, dried fruits (e.g., raisins), and enriched cereals and grains. Infant formulas are commonly fortified with iron in the US. Several therapeutic iron salts are available as supplements, including ferrous sulfate, ferrous gluconate, and ferrous fumarate. Some clinicians believe oral ferrous gluconate causes fewer adverse GI effects than does oral ferrous sulfate; however, this observation may be related to the lower amount of elemental iron in ferrous gluconate (12%) relative to ferrous sulfate (20%). Carbonyl iron is a form of elemental iron produced by a chemical carbonyl decomposition process. Carbonyl iron particles are small (e.g., 5 microns) and have large surface areas, which results in improved bioavailability relative to the iron salts. Ferrous sulfate was in use before 1938 and approved by the FDA at its inception.
For storage information, see the specific product information within the How Supplied section.
NOTE: Serum iron, hemoglobin and hematocrit should be evaluated prior to iron therapy and at regular intervals during therapy. Serum ferritin and transferrin-saturation may also be helpful monitoring parameters in some patients.
Adverse GI effects are common after oral administration of iron salts. Adverse effects can diminish with use and may be reduced by taking iron immediately after meals for a few days, even though this can reduce total iron absorption. Smaller, more frequent doses also can help. The most common adverse GI effects are constipation, abdominal pain, dyspepsia, stool discoloration, nausea, and vomiting. Although infrequent, GI irritation may be severe enough to cause anorexia or diarrhea in some patients.
Liquid preparations of iron salts can produce tooth discoloration, a superficial and temporary staining of tooth enamel. Iron can bind to tooth surfaces on contact, or may collect in plaque or etchings on tooth surfaces, thereby causing discoloration. The iron solutions may impart a grey color to the affected teeth. Diluting oral iron liquids with water or fruit juice and drinking the solutions through a straw will help minimize contact of the solutions with the enamel of the teeth. Proper oral hygiene can prevent or remove staining, as can brushing with baking-soda. Iron tablets and capsules do not stain the teeth.
Solid oral iron dosage forms may produce local oral ulceration, or esophagitis or esophageal ulceration, respectively, if held within the mouth or lodged within the larynx or esophagus. Iron-induced esophagitis is characterized by sudden onset odynophagia, retrosternal pain, and dysphagia. Other severe complications such as esophageal stricture, bleeding, and perforation have been reported. Risk factors for iron-induced esophageal effects include taking the medication without water and at night. Symptoms usually resolve within days to weeks after stopping the medication. The accidental inhalation of solid iron dosage forms into the lungs has been reported to cause bronchial ulceration and necrosis. These rare events can produce significant morbidity. 
Iron is not easily eliminated from the body and acute overdose may result in toxicity. Serum iron levels greater than 300 mcg/dl are potentially toxic. Elevated ferritin levels or transferrin oversaturation may also indicate iron poisoning. The clinical course of acute iron overdosage can be variable. Initial symptoms may include abdominal pain, nausea, vomiting, diarrhea, tarry stools, melena, hematemesis, hypotension, tachycardia, metabolic acidosis, hyperglycemia, dehydration, drowsiness, pallor, cyanosis, lassitude, seizures, shock and coma. Iron overload, which can occur after long-term use of iron, may cause exogenous hemosiderosis. Hemosiderosis is the result of deposition of hemosiderin, an iron-containing pigment, in the tissues of the liver and spleen. Hemosiderosis is rare with proper iron use; periodic monitoring of serum ferritin levels may be helpful in recognizing a progressive accumulation of iron resulting from impaired iron uptake from the reticuloendothelial system. Excessive chronic iron ingestion rarely, if ever, causes hemochromatosis unless a genetic predisposition to the disorder is also present (roughly <= 0.5% of the population). Hemochromatosis results in aberrations of iron metabolism and storage; iron accumulates in the body and excess iron deposition (hemosiderosis) occurs in the parenchymal tissues. With hemochromatosis, the liver becomes enlarged, and skin discoloration, specifically a bronze hue, occurs. Pancreatic dysfunction, diabetes mellitus, cardiac failure, liver failure and other tissue disorders may occur secondary to hemochromatosis.
Ferrous fumarate, an iron salt, has been associated with acute generalized exanthematous pustulosis (AGEP). The nonfollicular, pustular, erythematous rash starts suddenly, is associated with fever above 38 degrees C, and is distinct from pustular psoriasis, although biopsy results in each reveal spongiform subcorneal pustules. Drugs are the main cause of AGEP. A period of 2—3 weeks after an inciting drug exposure appears necessary for a first episode of AGEP. Unintentional reexposure may cause a second episode within 2 days. Clinical presentation is diverse with cutaneous lesions beyond erythema and pustules present in half of the cases. For example, bullous lesions, edema, purpura, pruritus, and mucosal erosions are possible. The mean duration of the pustules is 9.7 days followed by an annular desquamation, as long as the causative drug or factor is discontinued. The physiopathological mechanisms of AGEP have not been determined but the pathological criteria of edema, leukocytoclastic vasculitis, eosinophil exocytosis, and keratinocyte focal necrosis are distinctive. Pustule confluence or very small pustules may lead a clinician to make an incorrect diagnosis of TEN, of drug-induced erythroderma, or of staphylococcal scalded skin syndrome.
Iron salts are only useful for those anemia types where iron-deficiency co-exists. The type of anemia and the underlying cause or causes should be determined before starting therapy with iron. Unnecessary administration of iron salts may lead to iron overload and iron toxicity. Since anemia may be a result of a systemic disturbance, such as recurrent blood loss, the underlying cause(s) should be corrected, if possible. Exogenous Iron salts are only useful for those anemia types where iron-deficiency co-exists. The type of anemia and the underlying cause or causes should be determined before starting therapy with iron. Unnecessary administration of iron salts may lead to iron overload and iron toxicity. Since anemia may be a result of a systemic disturbance, such as recurrent blood loss, the underlying cause(s) should be corrected, if possible. Exogenous administration of iron salts will not alleviate hemolytic anemia and should only be administered to patients with hemolysis if an iron-deficiency is also present. Iron supplementation should be used cautiously in patients receiving blood transfusions because iron overload may occur.
Administration of iron salts to premature neonates can increase the risk of developing hemolytic anemia because these neonates may have a low vitamin E serum concentration. In general, iron supplementation should not begin until adequate vitamin E is supplied in the diet; human breast milk and modern infant formulas usually supply adequate dietary vitamin E.
Infants and children should receive iron salts only under the advice and supervision of a qualified health care professional. Accidental exposure to excessive amounts of iron-containing products (i.e., overdose) is the leading cause of fatal poisoning in children under the age of 6 years. Products that contain 30 milligrams (mg) or more of iron per dosage unit are packaged as individual unit-doses. This is to limit the number of pills or capsules a small child could accidentally consume once the package is opened. The FDA published the final rule on the packaging of iron in the January 15, 1997 Federal Register. Under U.S. Consumer Product Safety Commission regulations, most drugs and dietary supplements with more than 250 mg of iron per container must have child-resistant packages. Always store any iron-containing products out of the reach of children and pets. In the case of accidental exposure by ingestion, call a physician or poison control center immediately.
Those suffering from hereditary/genetic hemochromatosis or hemochromatosis due to secondary iron overload (e.g., as in iron-loading anemias such as thalassemia or sideroblastic anemia) need to avoid iron salts and other iron supplements. Hemochromatosis causes the body to lose its ability to regulate the amount of iron that is absorbed, leading to excess iron absorption and tissue storage. Massive deposition of iron (hemosiderosis) in parenchymal tissues in these conditions may damage the liver, heart, pancreas and other tissues. Porphyria cutanea tarda (PCT) is sometimes associated with parenchymal iron deposits; patients with PCT should avoid iron supplements unless prescribed by a physician. Excess iron supplementation in patients with PCT can contribute to hepatic uroporphinogen decarboxylase deficiency, but the mechanism is not clear. Some patients with chronic hepatic disease may have hemochromatosis or moderate iron overload in hepatic tissues. The liver is one of the main storage sites for iron, and advanced chronic liver disease may result in excess storage iron in the liver. Thus patients with hepatic disease should receive iron supplementation with caution and only under the direction of a health care prescriber.
Orally administered iron salts may have a corrosive effect that may exacerbate the symptoms associated with certain GI disease states such as peptic ulcer disease or inflammatory bowel disease (e.g., ulcerative colitis). Patients with dysphagia have, on rare occasions, developed oral or esophageal ulcerations from difficulty in swallowing solid oral iron dosage forms. Iron salts may produce constipation and should be used with care in patients with GI obstruction or ileus. Iron products may cause false-positive results on stool guaiac tests for blood.
When ingested in amounts according to the recommended daily allowances (RDA), iron salts are considered safe for use during pregnancy. Routine iron supplementation during pregnancy appears to prevent low maternal hemoglobin at birth and in the immediate postpartum period. The effect of routine iron supplementation on fetal or maternal outcomes is not clear, but is thought to be beneficial. Pregnant women should supplement iron salts during pregnancy only when advised to do so by a qualified health care professional. 
Use of iron supplements within the recommended daily dietary intake for lactating women is generally recognized as safe. While iron is excreted into breast-milk, the iron content of breast milk is not readily affected by the iron content of the maternal diet or the maternal serum iron level. Therefore, the use of iron salts, under the direction of a health care prescriber, is compatible with breast-feeding if the lactating mother needs treatment for iron deficiency. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.
Some iron products contain sulfites and should be used with caution in patients with a known sulfite hypersensitivity. Although the overall prevalence of sulfite hypersensitivity is low, it is seen more frequently in asthmatics or in atopic non-asthmatic persons.
Normal erythropoiesis is dependent on the concentration of iron and erythropoietin available in the plasma. Approximately two-thirds of total body iron is in the circulating red blood cell mass as hemoglobin, the major factor in oxygen transport. Administration of iron does not stimulate the production of red blood cells, nor does it correct abnormalities not caused by iron deficiency. A therapeutic response to treatment with iron products is dependent on the patient's ability to absorb and use the iron. The response to iron therapy is also influenced by the cause of the deficiency as well as other illnesses that can affect normal erythropoiesis. A positive response to iron treatment can be noted by an increase in the reticulocyte count within 1 week of therapy and an increase in hemoglobin at roughly 3—4 weeks, assuming that transfusion or other interventions cannot explain the improvements in the patients clinical status.
Iron-containing proteins and enzymes are important in oxidation-reduction reactions, especially those of the mitochondria. Iron is a component of myoglobin and several heme-enzymes, including the cytochromes, catalase, and peroxidase. Iron is an essential component of the metalloflavoprotein enzymes and the mitochondrial enzyme alpha-glycerophosphate oxidase. Furthermore, iron is a cofactor for enzymes such as aconitase and tryptophan pyrrolase. Iron deficiency not only causes anemia and decreased oxygen delivery, it also reduces the metabolism of muscle and decreases mitochondrial activity. Iron deficiency can also lead to defects in learning or thermoregulation. Thus iron is important to several metabolic functions which are independent of its importance to erythropoiesis.
Iron salts are administered orally. Once absorbed, the amount of total body iron content is used to form essential iron-dependent compounds and any excess iron is stored. Most of the essential iron in the body is contained in hemoglobin. Roughly 80% of plasma iron goes to the bone marrow to produce new erythrocytes. Other iron-dependent essential compounds include myoglobin and iron-dependent enzymes. The internal transport of iron to essential sites depends on the plasma protein transferrin. Transferrin delivers iron to specific transferrin receptors at target tissues, which then deliver iron to intracellular sites. Transferrin is extruded from the cell once iron is delivered intracellularly. The production of transferrin receptors is regulated according to body needs; when iron is deficient, transferrin receptors increase and iron storage via ferritin decreases. Ferritin is the storage protein for iron. The main sites of iron storage are the liver, spleen, bone marrow, and the reticuloendothelial system; a minor portion is stored in the muscle. After a life-cycle of roughly 120 days, roughly 0.8%/day of the circulating erythrocytes are catabolized by the reticuloendothelial system (RES); at that time, some of the iron is recirculated to the plasma bound to transferrin. The remaining iron from erythrocyte breakdown is incorporated into ferritin stores in the RES and hepatocytes. The utilization of iron by the body is designed to maintain body stores, so very little physiologic loss of iron occurs once it is in the body. In healthy adults, daily loss of iron occurs primarily through GI losses (e.g., bile, exfoliated mucosal or red cells); minor amounts are lost through skin desquamation or the urine. Physiologic losses in adult males average roughly 1 mg/day. Iron status will determine the magnitude of iron loss; less iron is lost in those individuals with iron deficiency. Those patients with excessive iron intake may lose up to 2 mg/day.
When iron is taken orally, the acidic environment of the stomach maintains iron in its more soluble ferrous (and more readily absorbed) state. Iron is then absorbed through the duodenum and upper small intestines. Although orally administered iron is absorbed in the duodenum, iron directly instilled into the duodenum is poorly absorbed. Intraduodenal pH is much higher than intragastric pH due to the high concentration of pancreatic secretions in the duodenum. Both ascorbic acid and meat (heme iron) will increase the absorption of non-heme iron. A hematopoietic transcription factor, known as NF-E2, regulates the absorption of iron by the oral route in response to erythropoiesis. Increased oral uptake into the systemic circulation occurs when iron deficiency or increased erythropoiesis (e.g., epoetin alfa therapy) is present. When iron stores are adequate, less iron is absorbed across the intestinal mucosa. The absorptive process across the intestine is finite, limiting the amount of entry of iron into the systemic circulation on a daily basis, even in deficiency. Oral iron absorption rarely exceeds 2 mg/day.
Some patients with chronic liver disease may exhibit excessive iron storage; use with caution in this population.
Iron is not hemodialyzable.
The hematopoietic systems of the fetus in utero and the neonate are complex. Premature infants are borne with defective erythropoiesis and without adequate iron storage and may develop a condition known as anemia of prematurity. Thus, premature infants generally have increased iron requirements relative to term infants. Term infants have adequate iron stores from birth to roughly age 6 months; after that time iron needs must be met by the diet.
Men have roughly twice the body iron stores compared to women. Menstruating women have an increased loss of iron as compared to adult males, as do other persons with loss of blood. Pregnancy increases iron-intake requirements.
Patients with partial gastrectomy or with malabsorption syndromes will have impaired absorption of iron from food.
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