VA Class:TN410

AHFS Class:

• Iron Preparations 20:04.04

Generic Name(s):

• Ferric Pyrophosphate

• Ferrous Gluconate

• Ferrous Sulfate

• Ferrous Sulfate, Dried

• Ferrous Fumarate

• Ferrous Carbonate

• Polysaccharide-Iron Complex

Ferrous fumarate, ferrous gluconate, ferrous sulfate, carbonyl iron, and polysaccharide-iron complex are iron preparations that are commercially available in the US for oral administration in the prevention and treatment of iron deficiency.

Iron Deficiency

Iron preparations are used for the prevention and treatment of iron deficiency. Iron will not correct hemoglobin disturbances caused by conditions other than iron deficiency but may cause iron toxicity or iron storage disease if used in these conditions. Iron also is not indicated for the treatment of anemia resulting from causes other than iron deficiency.

Ensuring adequate dietary iron intake is the principal means for primary prevention of iron deficiency in all age groups, reserving iron supplementation for individuals and groups at high risk of deficiency and/or in whom adequate dietary intake is unlikely to be achieved and iron therapy for those with presumed or established iron-deficiency anemia.101,109,133 Oral administration is the route of choice for iron therapy in most patients and for iron supplementation. Because they appear to be the most readily absorbed, ferrous salts are the iron preparations of choice. Since absorption of iron salts occurs maximally in the duodenum and proximal jejunum, extended-release or enteric-coated preparations should be used only if objective bioavailability data have shown the preparation to be effective and if the potential benefits outweigh the disadvantage of added cost.

Iron deficiency is the most common known nutritional deficiency.109,133 Deficiency of iron may result from inadequate ingestion, decreased absorption or utilization, abnormal blood losses (including menstruation), or increased requirements. When a diagnosis of iron deficiency is confirmed, a cause must be identified. Iron deficiency represents a spectrum ranging from iron depletion, which results in no physiologic impairment, to anemia, which affects the functioning of several organ systems.109 In depletion, the amount of stored iron is reduced but the amount of functional iron (e.g., in hemoglobin) may not be affected;109 if body requirements increase in depleted individuals, there are no stores from which to mobilize iron.109 Erythropoiesis in iron deficiency depletes iron stores and reduces transport iron further; GI absorption of iron is insufficient to replace the amount depleted or to provide the amount needed for growth and function.109 As a result, erythrocyte production is limited and erythrocyte protoporphyrin concentration increases secondarily.109 In iron-deficiency anemia, the most severe form of deficiency, the iron shortage results in inadequate production of iron-containing functional compounds, including hemoglobin;109 erythrocytes are microcytic and hypochromic.109 In the treatment of iron deficiency, administration of iron in combination with other minerals and/or vitamins has not been established as being superior to iron alone.

Risks and Prevalence of Iron Deficiency

Despite recent improvements (e.g., secondary to increased use of iron-fortified formulas in nonbreast-fed infants), iron deficiency remains relatively prevalent in the US in adolescent girls and women of childbearing age and in infants.109,125,133 Considerable morbidity, particularly among young children and pregnant women, can result from iron deficiency, and efforts to prevent, detect, and treat iron deficiency should be heightened in the US, especially among such individuals and females of childbearing age.109,131,133 Because some developmental deficits in young children may not be fully reversible, the importance of primary prevention in this age group is particularly important.133

Infants and Young Children

Iron-deficiency anemia can result in considerable morbidity in young children.109,115,116,117,118,131,133 In infants and preschool children up to 5 years of age, iron-deficiency anemia results in developmental delays and behavioral disturbances (e.g., decreased motor activity, social interaction, and attention to tasks).109,115,116,117,131,133,131 Such developmental delays may persist beyond 5 years of age into the school years if the iron deficiency is not reversed fully, and some developmental deficits may not be fully reversible even with iron therapy.109,115,116,117,133 The effects of mild iron-deficiency anemia on infant and early childhood development and behavior remain to be further elucidated.109,118 Iron-deficiency anemia also may enhance the risk of lead toxicity in children by increasing GI absorption of heavy metals, including lead.109,118,133 Iron-deficiency anemia in young children also may be associated with conditions (e.g., low birthweight, undernutrition, poverty, high blood lead concentrations) that independently affect development, and such potential confounding factors should be considered when interventions aimed at managing iron-deficiency anemia are developed and evaluated.109,117,133

Rapid growth rate combined with frequently inadequate dietary iron intake places children younger than 2 years of age, particularly those 9-18 months of age, at the highest risk of any age group for iron deficiency.109,133 Iron stores of full-term infants generally meet iron requirements until 4-6 months of age,109,131,133 and iron-deficiency anemia generally does not become evident until about 9 months of age.109 However, iron stores can be depleted by 2-3 months of age in premature or low-birthweight infants secondary to lower iron stores at birth and more rapid growth during infancy, placing such infants at greater risk for iron deficiency than full-term infants with normal or high birthweight.109,131,133

In the US, iron deficiency occurs in about 9% of children 12-36 months of age, in about one-third of whom the deficiency has progressed to anemia.109,125 The prevalence of iron deficiency is greater in children living at or below the poverty line than in those living above the poverty line and also is greater in blacks and Mexican-Americans than in white children.109,125

The iron content and absorption efficiency of various milk sources and feeding practices are a strong predictor of iron nutritional status during the first year of life.109,133

Breast milk has the highest percentage of bioavailable iron (about 50%),109,133 and breast milk and iron-fortified formula can provide adequate iron to meet an infant's iron requirements.109,133 However, the relatively high iron bioavailability of breast milk does not completely compensate for the relatively low iron content.133 Although iron-fortified formula has a relatively low iron bioavailability (about 4%), it has a substantially higher iron concentration than breast milk, which can compensate for differences in bioavailability.109,133 Nonfortified-formulas and whole cow's milk have an iron bioavailability of about 10% but relatively low iron concentrations (especially cow's milk).109,133

Although most nonbreast-fed infants in the US appear to receive the recommended dietary allowance of iron through diet,109 20-40% of infants fed nonfortified formula or whole cow's milk are at risk for iron deficiency by 9-12 months of age, while those fed mainly iron-fortified formula are unlikely to have deficiency (e.g., about an 8% risk).109,126,133 In addition, 15-25% of US breast-fed infants are at risk for iron deficiency by 9-12 months of age,109,126,133 and more than 50% of US children 1-2 years may not be receiving adequate dietary iron.109 Consumption of iron-fortified cereal can reduce the risk of iron deficiency in infants.109,127 Although the effect of prolonged exclusive breast-feeding on iron status remains unclear,109 limited evidence suggests that exclusive breast-feeding for longer than 7 months minimizes the risk of iron deficiency relative to breast-feeding that is supplemented by nonfortified foods beginning at 7 months of age or younger.109,128 Introduction of whole cow's milk before 1 year of age or consumption of more than 720 mL (24 oz) after the first year of life increases the risk of iron deficiency because such milk has little bioavailable iron, may displace the desire for foods with higher iron content, and may cause occult GI bleeding;109,126,129,130,133 goat's milk109,133 is likely to carry a similar risk because of similar iron composition to whole cow's milk,109 and soy milk (not iron-fortified soy-based formula) also should be avoided for the milk-based part of the diet before 12 months of age.133 Because iron-fortified formulas are readily available, do not cost much more than nonfortified formulas, and have few proven adverse effects other than dark stools,109,131,132,133 they are preferred for primary prevention of iron deficiency in nonbreast-fed or partially breast-fed infants younger than 1 year old as well as for weaning breast-fed infants in this age group; no common medical indication exists for the use of low-iron formulas.109,133

The risk of iron deficiency declines after 24 months of age because growth velocity slows, the diet becomes more diversified, and iron stores start to accumulate.109,125,133 After 36 months of age, dietary iron and iron status usually are adequate.109,125 However, iron deficiency can develop in either age group as a result of limited access to food (e.g., because of low income or migrant or refugee status), a low-iron or other specialized diet, or a medical condition that affects iron status (e.g., inflammatory or bleeding disorders).109,125

Females of Childbearing Age and Adolescents

In adolescents 12 up to 18 years of age, iron requirements and the risk of iron deficiency increase because of rapid growth.101,109 Among boys, the risk subsides after the peak pubertal growth period.109 However, among girls and women, menstruation increases the risk of iron deficiency throughout childbearing years.109 In addition, heavy menstrual blood loss (80 mL or more monthly) is an important risk factor for iron-deficiency anemia in women, affecting about 10% of such women in the US.109 Other risk factors for iron deficiency include use of an intrauterine device (secondary to increased menstrual blood loss), high parity, previous diagnosis of iron-deficiency anemia, and low iron intake.109,125 Oral contraceptive use is associated with a decreased risk of iron deficiency.109,141 Only about 25% of adolescent girls and women of childbearing age (12-49 years old) achieve the recommended dietary allowance of iron through diet,109 and 11% of nonpregnant women 16-49 years of age experience iron deficiency, in about 25-50% of whom the deficiency has progressed to anemia.109,125

Pregnancy

During the first and second trimester of pregnancy, iron-deficiency anemia is associated with a twofold increased risk of premature delivery and a threefold increased risk of a low-birthweight delivery.109,120 Although iron supplementation during pregnancy has been shown to decrease the incidence of anemia,109,121,122 evidence on the effect of routine iron supplementation during pregnancy on adverse maternal and infant outcomes is inconclusive.109,123,124 Blood volume expands by about 35% during pregnancy, and growth of the fetus, placenta, and other maternal tissues increases the iron requirement threefold during the second and third trimesters of pregnancy to about 5 mg of iron daily.101,109 Although menstruation ceases and iron absorption increases during pregnancy, most pregnant women who do not use iron supplements to meet increased iron requirements cannot maintain adequate iron stores, particularly during the last 2 trimesters.109 Following delivery, iron in the fetus and placenta are lost to the woman, although some of the iron in the expanded blood volume may return to blood stores.109 Among low-income pregnant women enrolled in health programs in the US, the prevalence of iron-deficiency anemia is 9, 14, and 37% during the first, second, and third trimesters, respectively.109 While similar data currently are not available for all pregnant women in the US, the low dietary iron intake among US women of childbearing age, the high prevalence of iron deficiency and associated anemia among such women, and the increased iron requirements during pregnancy101,109,125 suggest that anemia during pregnancy may extend beyond low-income women.109 In addition, use of prenatal multivitamin and mineral supplements among African-Americans, native American and Alaskan Indians, women younger than 20 years of age, and those having less than a high school education is substantially lower than in the general US pregnant population.109,142,143

The principal reasons for the current lack of widespread adoption of a recommended iron supplementation regimen during pregnancy in US women may include lack of health-care provider and patient perceptions that iron supplements improve maternal and infant outcomes, complicated dose schedules, and adverse effects (e.g., constipation, nausea, vomiting).109,142 However, adequate dietary iron intake and iron supplementation generally are recommended for primary prevention of iron deficiency during pregnancy.109,148 By employing low-dose (i.e., 30 mg of iron daily) regimens with simplified dose schedules (i.e., once-daily dosing), patient compliance may be improved;101,109 low-dose regimens have been shown to increase patient tolerance and are as effective as higher dosages (e.g., 60-120 mg iron daily) in preventing iron-deficiency anemia.101,109,142

Other Adults

In adults 18 years of age and older, effects of iron-deficiency anemia on daily functioning may be less overt than in children.109,137 Such anemia in laborers (e.g., tea pickers, latex tappers, cotton mill workers) in developing countries can impair work capacity, which appears to be at least partially reversible with iron therapy.109,119 Whether iron-deficiency anemia in adults affects the capacity to perform less physically demanding labor that depends on sustained cognitive or coordinated motor function remains to be elucidated.109,135,136 Iron-deficiency anemia also can manifest as impaired exercise capacity,131 lethargy,137 and dyspnea.137 Skin, nail, and other epithelial changes of chronic iron deficiency include atrophic changes of the skin, nail changes such as koilonychia (spoon-shaped nails) that manifest as brittle flattened nails, angular stomatitis (i.e., painful fissuring at the angles of the lips), glossitis, and esophageal and pharyngeal webs with associated dysphagia.101,131,137

Iron-deficiency anemia is uncommon in the US among males 18 years of age and older and among postmenopausal women.109,125 The incidence of this anemia in the US is 2% or less among males 20 years of age and older and 2% among postmenopausal women.109,125 Most adults in the US with iron-deficiency anemia have GI bleeding secondary to lesions (e.g., ulcers, tumors),109,144 and about two-thirds of anemia cases among men and postmenopausal women were attributable to chronic disease or inflammatory conditions;109,145 therefore, iron-deficiency anemia in adults, unlike that in children or women of childbearing age, appears to be caused principally by an underlying disease rather than by low iron intake.109,144,145

Prevention and Treatment of Iron Deficiency

Primary prevention of iron deficiency involves ensuring adequate dietary intake of the mineral in all age groups, and selective use of iron supplementation (e.g., in individuals or groups at high risk or when adequate dietary intake is unlikely to be achieved).109,133 Primary prevention of iron deficiency is particularly important in children younger than 2 years of age and in women (including adolescents) of childbearing age, including those who are or who are not pregnant.101,109,125,131,133,148 Secondary prevention involves screening for, diagnosing, and treating iron deficiency.101,109,131,133

Prevention of Deficiency

The normal US diet, which provides about 12 mg of iron per 2000 calories, is usually sufficient to maintain iron equilibrium in normal adult men and postmenopausal women. Fish, meat (especially liver), and fortified cereals and bread are the best dietary sources of iron. Dietary intake of iron is inadequate and prophylactic iron is required during the first year of life in infants whose diet consists largely of milk and in pregnant women; dietary iron may be marginal in menstruating women. Prophylactic iron therapy may also be required in chronic blood donors. Hemodialysis patients who are receiving therapy with an erythropoiesis-stimulating agent (ESA) (e.g., epoetin alfa, darbepoetin alfa) for anemia of chronic kidney disease may not respond adequately to oral iron therapy and may require parenteral (IV) iron replacement therapy.149,150,151,152,153,154,199,200 (See Treatment of Anemia, under Uses: Prevention and Treatment of Iron Deficiency.)

Infants and Young Children

Primary prevention of iron deficiency is most important in children younger than 2 years of age because this age group is at greatest risk for deficiency secondary to inadequate iron intake.101,109,125,126,131,133 To minimize the risk of iron deficiency in infants, exclusive breast feeding (without supplemental liquid, formula, or food) should be encouraged for 4-6 months after birth.109 In premature or low birthweight (less than 2.5 kg) breast-fed infants, prophylactic iron supplementation with 2-4 mg/kg (not exceeding 15 mg) daily should be initiated by at least 2 months, preferably at 1 month, of age.

When exclusive breast-feeding is stopped in full-term infants, an additional source of iron should be used (about 1 mg/kg daily of iron), preferably from supplementary foods (e.g., iron-fortified formula and/or cereals).109,133 In normal full-term infants, iron stores are usually adequate during the first few months of life, but prophylactic iron should be initiated when the infant is about 4-6 months of age.109,133 Infants who are not breast-fed or who are only partially breast-fed should receive prophylactic iron, preferably as iron-fortified formula, usually beginning at birth and continuing during the first year of life; iron-fortified formula should be the only type of infant formula used during this period, regardless of when formula-feeding is started.109,133 For breast-fed infants who receive insufficient iron from supplementary foods by 6 months of age (i.e., less than 1 mg/kg daily), iron supplementation (e.g., 1 mg/kg daily) is suggested.109,133 If breast-feeding is not possible, only iron-fortified formulas should be used during the first year of life, supplementing the formula with foods beginning at 4-6 months of age or once the extrusion reflex disappears.109,133

To improve iron absorption, one feeding daily preferably should include foods rich in ascorbic acid (vitamin C) (e.g., fruits, vegetables, juices), by approximately 6 months of age, given with meals if possible.109 Plain pureed meats can be introduced to the diet after 6 months of age or when the infant is developmentally ready to consume such food.109,133 (See Cautions: Adverse Effects.) Although infants' iron requirements may be provided by use of iron-containing infant formulas or cereals, these preparations should not be relied upon to treat iron deficiency if it occurs. Consumption of regular cow's, goat's, or soy milk should be limited to 720 mL (24 oz) daily in children 1-5 years of age.109,133

Older Children and Adolescents

Because of slight increases in iron requirements associated with increases in iron mass related to growth in body size, children and adolescents approximately 10 years of age and older may require prophylactic iron during the pubertal growth spurt and with the start of menstruation in females. However, most adolescents, including menstruating girls, do not require iron supplementation; instead, consumption of iron-rich foods and foods that enhance GI iron absorption should be encouraged.109

Pregnant Women

Primary prevention of iron deficiency in pregnant women requires adequate dietary iron intake and iron supplementation.109 Although conclusive evidence of the benefits of routine iron supplementation for all women currently is lacking,109 routine prophylactic iron supplementation currently is recommended for all pregnant women because a large proportion of such women experience difficulty in maintaining iron stores during pregnancy,109,112,146,148 iron-deficiency anemia during pregnancy is associated with adverse outcomes,109,120 and such supplementation during pregnancy is not associated with important health risks.109,142

Prophylactic iron supplementation during pregnancy should be initiated with oral, low-dose (30 mg daily) iron at the initial prenatal visit.109,148 Pregnant women also should be encouraged to consume iron-rich foods and foods that enhance GI iron absorption.109 Pregnant women with low-iron diets should be counseled about optimizing dietary iron intake.109 If no risk factors for iron deficiency are present at delivery, iron supplementation should be discontinued.109 Iron supplementation is particularly important for pregnant women who are vegetarians.109 Women at risk for anemia should be screened postpartum and treated as necessary.109

Patients with Anemia of Chronic Kidney Disease

Almost all patients with chronic kidney disease who receive therapy with an ESA (e.g., epoetin alfa, darbepoetin alfa) will require iron therapy because of the dramatic decrease in iron stores associated with erythrocyte formation.151,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175,176,177,178,179,180,181,182,199,200 Although chronic kidney disease patients with iron overload prior to starting ESA therapy may not require iron supplementation initially, profound iron deficiency may develop subsequently, so monitoring of serum and tissue iron stores is essential during therapy with the drug.149,199,200 Supplemental iron should be administered to prevent iron deficiency and to maintain adequate iron stores in patients with chronic kidney disease who are receiving ESA therapy.149,199,200 (See Uses: Anemia of Chronic Kidney Disease and also see Cautions: Precautions and Contraindications, in Epoetin Alfa 20:16.)

Most hemodialysis patients receiving ESAs require IV iron to maintain iron stores.149,199,200 (See Treatment of Anemia, under Uses: Prevention and Treatment of Iron Deficiency.) Even though a temporary improvement in hematocrit may occur with oral iron therapy, iron depletion resulting from blood loss exceeds the absorption of iron from oral supplements in most ESA-treated hemodialysis patients, and iron stores eventually decrease (as indicated by decreasing serum ferritin concentrations).149,199,200 As negative iron balance continues, iron stores decrease and become inadequate.149 Although GI absorption of iron does not appear to be impaired in patients with chronic kidney disease, only a small fraction of orally administered iron is absorbed even in individuals without the disease.149,199 Consequently, 200 mg of elemental iron (approximately two 325-mg tablets of ferrous fumarate or three 325-mg tablets of ferrous sulfate) ingested daily usually cannot meet the demands of epoetin alfa-induced erythropoiesis in hemodialysis-associated blood losses.149 Inadequate absorption of oral iron is exacerbated by the fact that patient compliance with oral iron regimens is often poor due to the inconvenience of dosing (i.e., 1 hour before or 2 hours after meals for optimal absorption), adverse effects such as GI irritation and constipation, and costs of therapy.149,199,200,201,202,203

Some clinicians state that a small percentage of hemodialysis patients, and many predialysis or peritoneal dialysis patients, are able to maintain adequate iron stores using only oral iron supplements, perhaps as a result of augmented intestinal iron absorption, smaller blood losses, and/or lower epoetin alfa requirements.149,200

Other Adults

Most nonpregnant women of childbearing age also do not require iron supplementation, but instead primary prevention of iron deficiency should be through dietary means, encouraging the consumption of iron-rich foods and foods that increase GI iron absorption.109 Although women with low-iron diets are at additional risk for iron deficiency, counseling such women about optimizing dietary iron intake can be sufficient.109 Men 18 years of age and older and postmenopausal women usually do not require iron supplementation.109

Screening for Anemia

Routine screening currently is recommended by the US Centers for Disease Control (CDC)109 and American Academy of Pediatrics (AAP)133 for all infants and children from populations at high risk of iron-deficiency anemia (e.g., those from low-income families, children eligible for the Special Supplemental Nutrition program for Women, Infants, and Children [WIC], recently arrived refugees) beginning at 9-12 months of age and then 6 months later (i.e., at 15-18 months of age) and annually thereafter from 2-5 years of age. AAP also considers routine screening an option for all full-term infants, regardless of risk, beginning at 9-12 months of age and repeated 6 months later at 15-18 months of a continued routine screening beyond this period is not recommended for the general pediatric population because few children older than 2 years of age develop iron deficiency.133

Selective screening is recommended by CDC109 and AAP133 for selected individuals who reside in communities or under circumstances where the incidence of anemia is low (e.g., 5% or less) and there generally are good dietary practices relative to iron intake but who nonetheless are at risk for iron deficiency. Selective screening is targeted at subsets of children who have a less than satisfactory diet or have special health-care needs and should follow the same schedule as routine screening.109,133 Selective screening is recommended for premature or low-birthweight infants, infants fed a diet of nonfortified formula for longer than 2 months, infants introduced to cow's milk before 12 months of age, breast-fed infants whose supplementary diet does not provide adequate iron after 6 months of age, children who consume more than 720 mL (24 oz) of cow's milk daily, and those with special health-care needs such as conditions that interfere with iron absorption, chronic infection, inflammatory disorders, restricted (e.g., nonmeat) diets, or excessive blood loss from a wound, accident, or surgery.109,133 Although anemia screening before 6 months of age generally is of little value for detecting iron deficiency because iron stores are adequate for most infants, premature or low-birthweight infants who are not fed iron-fortified formula may benefit from beginning screening before 6 months of age.109,133 Children 2-5 years of age not previously identified as being at risk for iron deficiency should be assessed annually for risk factors (e.g., low-iron diet, limited access to food because of poverty or neglect, special health-care needs), screening those who have any such identifiable risk.109

Because preadolescent school-age children 5 years of age and older in the US, other than those receiving a very restrictive diet, are at lower risk for iron deficiency than are younger children, routine screening for anemia in this age group is not recommended.109,133 Instead, anemia screening should be employed selectively .109,133 Children in this age group who consume a strict vegetarian diet should be screened for iron-deficiency anemia133 as should those with a history of iron-deficiency anemia, special health-care needs, or low iron intake.109 Likewise, adolescent males 12 up to 18 years of age generally should be screened selectively,109,133 although screening also can be considered during a routine physical examination that coincides with the peak growth period.133 Iron deficiency is particularly common in children consuming vegan diets, but is less common in lacto-ovo vegetarians.133

All nonpregnant females should be screened for iron-deficiency anemia during all routine adolescent physical examinations133 and every 5-10 years throughout their childbearing years as part of routine health examinations.109 In addition, women with risk factors for anemia (e.g., extensive menstrual or other blood loss, low iron intake, history of iron-deficiency anemia) should be screened annually.109

Pregnant women should be screened for iron-deficiency anemia during the initial prenatal visit.109 Postpartum women at risk for anemia also should be screened 4-6 weeks postpartum.109

Routine screening for iron-deficiency anemia is not recommended for males 18 years of age and older or for postmenopausal women.109 Iron deficiency or anemia suspected or detected during routine medical examinations should be evaluated fully.109

Treatment of Anemia

Presumed or confirmed iron-deficiency anemia should be treated with iron, preferably with oral preparations in most patients.109,133 However, hemodialysis patients with anemia of chronic kidney disease who are receiving epoetin alfa may have an inadequate response to oral iron and may require parenteral (IV) iron supplementation. (See Patients with Anemia of Chronic Kidney Disease, under Prevention and Treatment of Iron Deficiency: Treatment of Anemia, in Uses.)

Infants and Young Children

Iron-deficiency anemia can be treated presumptively in infants and preschool-age children with 3 mg/kg daily of iron;109,133 the parent or guardian should be counseled about adequate diet to correct the underlying problem of low iron intake.109 If anemia is confirmed by a repeat screening 4 weeks later, dietary counseling should be reinforced and iron treatment should continue for 2 more months, at which time testing should be repeated.109,133 Hemoglobin and hematocrit should be reassessed 6 months after completion of successful iron treatment.109 If iron deficiency is not corrected after 4 weeks of iron treatment in the absence of acute illness (e.g., otitis, diarrhea, upper respiratory tract infection), further diagnostic measures (e.g., mean corpuscular volume [MCV], erythrocyte distribution width [RDW], serum ferritin concentration) should be performed to determine whether the anemia is secondary to iron deficiency.109,133

Older Children and Adolescents

Preadolescent school-age children and adolescent boys up to 18 years of age can be treated presumptively for iron-deficiency anemia with a trial of iron;109,133 school-age children 5 up to 12 years of age can receive 60 mg of iron daily and adolescent boys can receive 120 mg daily.109 Follow-up and laboratory evaluation are the same as those for infants and preschool children.109 Menstruating adolescent girls 12 up to 18 years of age also can be treated presumptively for anemia109,133 with a trial of 60-120 mg of iron daily.109 Follow-up and laboratory evaluation are the same as those for infants and preschool children, except that iron treatment should continue for 2-3 months longer if anemia is confirmed.109 If iron deficiency is not corrected after 4 weeks of iron treatment in the absence of acute illness, further diagnostic measures (e.g., mean corpuscular volume [MCV], erythrocyte distribution width [RDW], serum ferritin concentration) should be performed to determine whether the anemia is secondary to iron deficiency.109

Pregnant Women

Iron-deficiency anemia can be treated presumptively in pregnant women with 60-120 mg of iron daily.109 However, if the hemoglobin concentration is less than 9 g/dL or hematocrit is less than 27%, the woman should be referred for further evaluation to a clinician familiar with anemia during pregnancy.109 If after 4 weeks the anemia does not respond to iron treatment to a level appropriate for the stage of pregnancy despite compliance with an iron treatment regimen in the absence of an acute illness, further diagnostic measures (e.g., mean corpuscular volume [MCV], erythrocyte distribution width [RDW], serum ferritin concentration) should be performed to determine whether the anemia is secondary to iron deficiency.109 When hemoglobin concentration becomes normal for the stage of pregnancy, iron treatment should be decreased to 30 mg daily.109 If hemoglobin concentration exceeds 15 g/dL or hematocrit exceeds 45% during the second or third trimester, the woman should be evaluated for potential pregnancy complications related to poor blood volume expansion.109

Iron-deficiency anemia in postpartum women should be treated the same as that in nonpregnant women of childbearing age.109

Patients with Anemia of Chronic Kidney Disease

Iron supplementation is required in virtually all patients with chronic kidney disease who are undergoing hemodialysis, particularly those receiving ESAs, because of the blood losses associated with hemodialysis and the increased demands for iron resulting from ESA-induced erythropoiesis.149,151,183,184,185,186,187,199,200 While some clinicians state that a trial of oral iron therapy is acceptable in hemodialysis patients,149 orally administered iron has been reported to be ineffective in maintaining adequate iron stores in such patients.149,200 To maintain and achieve adequate hemoglobin concentrations in hemodialysis patients,149 most of these patients receiving ESAs will require IV iron on a regular basis.149,199,200 (See Uses: Anemia of Chronic Kidney Disease and also see Cautions: Precautions and Contraindications, in Epoetin Alfa 20:16.) Oral iron therapy is not indicated for chronic kidney disease patients who requires maintenance doses of IV iron.149

In predialysis and peritoneal dialysis patients with minimal daily iron losses, provision of 200 mg of elemental oral iron per day may be sufficient to replace ongoing losses and support erythropoiesis.149

If oral iron is used, some experts state that use of one of the ionic iron salts, such as iron sulfate, fumarate, or gluconate, is preferable since these salts are inexpensive and provide known amounts of elemental iron.149 Well-controlled studies have not documented that iron polysaccharide is better tolerated (i.e., the incidence of nausea, vomiting, or abdominal discomfort leading to discontinuance is not reduced) than other iron salts.149

Other Adults

Nonpregnant women of childbearing age also can be treated presumptively for anemia with a trial of 60-120 mg of iron daily.109 Follow-up and laboratory evaluation are the same as those for infants and preschool children, except that iron treatment should continue for 2-3 months longer if anemia is confirmed.109 If iron deficiency is not corrected after 4 weeks of iron treatment in the absence of acute illness, further diagnostic measures (e.g., mean corpuscular volume [MCV], erythrocyte distribution width [RDW], serum ferritin concentration) should be performed to determine whether the anemia is secondary to iron deficiency.109 In women of African, Mediterranean, or Southeast Asian descent, mild anemia may be secondary to thalassemia minor or sickle-cell trait.109

Dietary Requirements

The National Academy of Sciences (NAS) has issued a comprehensive set of Recommended Dietary Allowances (RDAs) as reference values for dietary nutrient intakes since 1941.101 In 1997, the NAS Food and Nutrition Board (part of the Institute of Medicine [IOM]) announced that they would begin issuing revised nutrient recommendations that would replace RDAs with Dietary Reference Intakes (DRIs).101 DRIs are reference values that can be used for planning and assessing diets for healthy populations and for many other purposes and that encompass the Estimated Average Requirement (EAR), the Recommended Dietary Allowance (RDA), the Adequate Intake (AI), and the Tolerable Upper Intake Level (UL).188

The NAS has established an EAR and RDA for iron for adults, children and adolescents 1-18 years of age, and infants 7-12 months of age based on the need to maintain a normal functional iron concentration but only minimal stores.188 Physiologic requirements for absorbed iron were calculated by factorial modeling of the components of iron requirement.188 Components used as factors in the modeling include basal iron losses, menstrual losses, fetal requirements in pregnancy, increased requirement during growth for expansion of blood volume, and/or increased tissue and storage iron.188 An AI has been established for infants through 6 months of age based on the observed mean iron intake of infants fed principally human milk.188 (For a definition of Estimated Average Intake, Recommended Dietary Allowance, Adequate Intake, and other reference values for dietary nutrient intakes, see Uses: Dietary Requirements in Folic Acid 88:08.)

The principal goal of maintaining an adequate intake of iron in the US and Canada is to prevent the functional consequences of iron deficiency such as impaired physical work performance, developmental delay, cognitive impairment, or adverse pregnancy outcome.188 Adequate intake of iron usually can be accomplished through consumption of foodstuffs; however, women usually need iron supplementation during pregnancy.188 Iron is present in food as part of heme (meat, poultry, fish) or as nonheme iron (vegetables, fruits, milk, cereals).188 Most grain products in the US are fortified with iron, and about one-half of ingested iron is supplied by iron-fortified breads, cereals, and breakfast bars.188

For specific information on currently recommended AI and RDAs of iron for various life-stage and gender groups, see Dosage: Dietary and Replacement Requirements, under Dosage and Administration.

Administration

Oral iron preparations generally should be taken between meals (e.g., 1 hour before or 2 hours after a meal) for maximum absorption but may be taken with or after meals, if necessary, to minimize adverse GI effects.201,202,203 Patients who have difficulty tolerating oral iron supplements also may benefit from smaller, more frequent doses, starting with a lower dose and increasing slowly to the target dose, trying a different form or preparation, or taking the supplement at bedtime.149

Dosage

Dosage of oral iron preparations should be expressed in terms of elemental iron. The elemental iron content of the various preparations is approximately:

Treatment of Iron Deficiency

In general, large oral doses of iron, based on calculated deficiency, must be given because of the incomplete and variable absorption of these preparations. The usual therapeutic dosage of elemental iron for adults is 50-100 mg 3 times daily. Smaller dosages (e.g., 60-120 mg daily) also have been recommended, and may be particularly useful for minimizing GI intolerance, but the possibility that iron stores will be replenished at a slower rate should be considered. Iron-deficient children should receive elemental iron in a dosage of 3-6 mg/kg daily given in 3 divided doses. In patients with chronic kidney disease undergoing hemodialysis and receiving epoetin alfa therapy, some experts currently recommend oral iron in a daily dosage of at least 200 mg of elemental iron for adults and 2-3 mg/kg for children and state that the daily dosage should be given in 2 or 3 divided doses.149 For additional information, see Prevention and Treatment of Iron Deficiency: Treatment of Anemia, in Uses.

With usual oral therapeutic dosages of iron salts, symptoms of iron deficiency usually improve within a few days, peak reticulocytosis occurs in 5-10 days, and the hemoglobin concentration rises after 2-4 weeks. Hemoglobin production usually increases at a rate of 100-200 mg/dL of blood daily; normal hemoglobin values are usually attained in 2 months unless blood loss continues. Because iron stores remain depleted, recurrence of anemia may result if iron therapy is discontinued at this time. In the treatment of severe deficiencies, iron therapy should be continued for approximately 6 months.

If a satisfactory response is not noted after 3 weeks of oral iron therapy, consideration should be given to the possibilities of patient noncompliance, simultaneous blood loss, additional complicating factors, or incorrect diagnosis.

Prevention of Iron Deficiency

To prevent iron deficiency, pregnant women generally should receive daily iron supplementation sufficient to maintain the daily dietary iron intake at 30 mg. Normal full-term infants who are not breast-fed or are only partially breast-fed should receive supplemental iron, preferably as iron-fortified formula, in a dosage of 1 mg/kg daily starting at birth and continuing during the first year of life.109,133 Premature or low-birthweight infants require 2-4 mg/kg daily starting by at least 2 months, preferably at 1 month, of age. Infants of normal or low birthweight should not receive iron supplementation exceeding 15 mg daily. Children approximately 10 years of age and older who have begun their pubertal growth spurt may require daily iron supplementation of 2 and 5 mg daily in males and females, respectively. For additional information, see Prevention and Treatment of Iron Deficiency: Prevention of Deficiency, in Uses.

Dietary and Replacement Requirements

The Adequate Intake (AI) (see Uses: Dietary Requirements) of iron currently recommended by the National Academy of Sciences (NAS) for healthy infants through 6 months of age is 0.27 mg daily.188 The Recommended Dietary Allowance (RDA) of iron currently recommended by NAS for healthy children 7-12 months of age, 1-3 years, 4-8 years, or 9-13 years of age is 11, 7, 10, or 8 mg daily, respectively.188 The RDA of iron for boys 14-18 years of age is 11 mg daily, and the RDA for girls 14-18 years of age is 15 mg daily.188 The RDA for healthy men of all ages (19-70 years of age and those older than 70 years of age) is 8 mg of iron daily.188 The RDA for healthy women 19-50 years of age is 18 mg of iron daily, and the RDA for healthy women 51-70 years of age and those older than 70 years of age is 8 mg daily.188

The RDA of iron recommended by the NAS for pregnant women 14-50 years of age is 27 mg daily.188 The NAS recommends an RDA of 10 or 9 mg of iron daily for lactating women 14-18 or 19-50 years of age, respectively.188

GI Effects

Usual oral therapeutic dosages of iron preparations produce constipation, diarrhea, dark stools, nausea, and/or epigastric pain in approximately 5-20% of patients. GI intolerance of all iron preparations is mainly a function of the total amount of elemental iron per dose and of psychological factors. Adverse GI effects usually subside within a few days. If necessary, they can be reduced or eliminated by ingesting iron after meals instead of between meals, by reducing the daily dosage for a few days, or by decreasing the size of the individual dose and increasing the number of doses daily.

Claims for prolonged action and reduced incidence of adverse effects with extended-release and enteric-coated preparations are not well substantiated. The low incidence of adverse effects associated with these preparations may reflect the small amount of iron released or the low total dose of elemental iron.

Large amounts of iron exert a strong corrosive action on the GI mucosa. Administration of Fero-Gradumet^® has resulted in a perforated jejunal diverticulum in at least one patient and a Meckel's diverticulum with localized gangrene in at least one other patient. Liquid iron preparations may temporarily stain dental enamel or the membrane covering the teeth of infants.

Hemosiderosis

Long-term administration of large amounts of iron may cause hemosiderosis clinically resembling hemochromatosis, which is a genetic condition characterized by excessive iron absorption, excess tissue iron stores, and potential tissue injury. Iron overload is particularly likely to occur in patients given excessive amounts of parenteral iron, in those taking both oral and parenteral preparations, and in patients with hemoglobinopathies or other refractory anemias that might be erroneously diagnosed as iron deficiency anemia. Iron overload is associated with an increased susceptibility to certain infections (e.g., those caused by Vibrio vulnificus , Yersinia enterocolitica , or Y. pseudotuberculosis ).134 Iron overload also may adversely affect prognosis in patients infected with human immunodeficiency virus (HIV).138,139,140 Since there is no excretory mechanism for iron, therapeutic removal by repeated phlebotomy or long-term administration of deferoxamine is necessary to prevent or reverse tissue damage if hemosiderosis occurs.

Other Adverse Effects

Administration of iron preparations to premature infants who normally have low serum vitamin E concentrations may cause increased red cell hemolysis and hemolytic anemia. Therefore, vitamin E deficiency should also be corrected if possible. Because vitamin E may not be well absorbed from the GI tract in these infants and oral iron may reduce vitamin E absorption, IM administration of the vitamin may be advisable.

Precautions and Contraindications

Administration of iron for longer than 6 months should be avoided except in patients with continued bleeding, menorrhagia, or repeated pregnancies. Iron should not be used to treat hemolytic anemias unless an iron-deficient state also exists, since excess storage of iron with possible secondary hemochromatosis can result. Iron should not be administered to patients receiving repeated blood transfusions, since there is a considerable amount of iron in the hemoglobin of transfused erythrocytes. Some manufacturers state that iron preparations usually are contraindicated in patients with peptic ulcer, regional enteritis, or ulcerative colitis. Parenteral iron should not be administered concomitantly with oral iron therapy.

Although primary hemochromatosis has been considered a contraindication to iron preparations, there currently is no evidence that iron fortification of foods or the use of a recommended low-dose iron supplementation regimen during pregnancy is associated with increased risk for hemochromatosis-associated clinical disease.109,111 Even when dietary iron intake is approximately average, individuals with hemochromatosis-associated iron overload will require phlebotomy to reduce their iron stores.109,147

Because accidental overdosage of iron-containing preparations is a leading cause of fatal poisoning in children younger than 6 years of age,108,148 patients should be advised to keep such preparations out of reach of children.148 If accidental overdosage occurs, a poison control center or clinician should be contacted immediately.148

Because iron can increase the pathogenicity of certain microorganisms134,138,139,140 and has been postulated as potentially adversely affecting prognosis in certain HIV-infected individuals,138,139 some clinicians recommend that HIV-infected individuals who do not have documented iron-deficiency anemia avoid iron supplementation for the management of HIV-associated anemia.138,139

Fergon^® 225-mg tablets contain the dye tartrazine (FD&C yellow No. 5), which may cause allergic reactions including bronchial asthma in susceptible individuals. Although the incidence of tartrazine sensitivity is low, it frequently occurs in patients who are sensitive to aspirin.

Antacids and Other GI Drugs

Concurrent administration of antacids or aluminum-containing phosphate binders with oral iron preparations may decrease iron absorption. Antacids and oral iron preparations should be administered as far apart as possible.

Drugs such as H₂-receptor antagonists and proton-pump inhibitors increase gastric pH and possibly may decrease the GI absorption of oral iron preparations that depend on gastric acidity for dissolution and absorption.192,193,194,195,196,197,198 The clinical importance of this potential interaction has not been fully determined.193,195,197 Some clinicians recommend that oral iron preparations be given at least 1 hour prior to these drugs if concomitant therapy is necessary.195

Methyldopa

Results of one crossover study in healthy adults indicate that concomitant administration of a single oral dose of ferrous sulfate (325 mg) or ferrous gluconate (600 mg) can decrease oral absorption of methyldopa (500 mg) by 61-73%.106 In addition, concomitant administration of either oral iron preparation appears to affect metabolism of methyldopa since there was a 79-88% decrease in urinary excretion of free methyldopa and an increase in urinary excretion of the sulfate conjugate of the drug.106 When oral ferrous sulfate therapy (325 mg every 8 hours) was initiated in hypertensive patients receiving chronic methyldopa therapy (250 mg 1-3 times daily or 500 mg 3 times daily), there was an increase in blood pressure during concomitant therapy and an decrease in blood pressure when the oral iron preparation was discontinued.106 Although further study is needed to evaluate the clinical importance of this drug interaction, the fact that oral iron preparations apparently can decrease the hypotensive effect of methyldopa probably should be considered in situations when the drugs might be used concomitantly (e.g., pregnant women being treated for hypertension, geriatric patients with hypertension).106

Quinolones

Concomitant administration of oral preparations containing iron may interfere with oral absorption of some quinolone anti-infective agents (e.g., ciprofloxacin, norfloxacin, ofloxacin) resulting in decreased serum and urine concentrations of the quinolones.102,103,104,105 Therefore, oral preparations containing iron should not be ingested concomitantly with or within 2 hours of a dose of an oral quinolone.102,103,104,105 In one crossover study, concomitant administration of a single dose of oral ferrous sulfate complex with ofloxacin decreased the area under the concentration-time curve (AUC) of the anti-infective agent by 36%.105

Tetracyclines

Oral administration of iron preparations inhibits absorption of tetracyclines from the GI tract and vice versa, leading to decreased serum concentrations of both the antibiotic and iron. If simultaneous administration of the drugs is necessary, patients should receive the tetracycline 3 hours after or 2 hours before oral iron administration.

Thyroid Agents

Concomitant administration of ferrous sulfate (300 mg once daily) in patients with primary hypothyroidism receiving thyroxine replacement therapy (0.075-0.15 mg of l-thyroxine daily) resulted in an increase in serum concentrations of thyrotropin (thyroid-stimulating hormone, TSH) and increased signs and symptoms of hypothyroidism.107 Although the free thyroxine index (FTI) was decreased in some patients after 12 weeks of concomitant therapy, the extent of this reduction was not clinically important; free serum thyroxine concentration and resin triiodothyronine uptake (RT₃U) were not substantially affected by concomitant therapy.107 It has been suggested that thyroxine and ferrous sulfate (and possibly other oral iron preparations) may form an insoluble ferric-thyroxine complex in vivo resulting in decreased absorption of thyroxine.107 If concomitant administration of oral iron preparations and thyroxine replacement therapy is necessary (e.g., geriatric patients, premature infants, pregnant women), doses of the drugs probably should be administered at least 2 hours apart and thyroid function should be monitored.107

Vitamin C

Concurrent administration of more than 200 mg of ascorbic acid per 30 mg of elemental iron increases absorption of iron from the GI tract. However, most individuals are able to absorb orally ingested iron adequately without concurrent administration of ascorbic acid, and preparations containing iron and ascorbic acid may not contain sufficient quantities of ascorbic acid to substantially affect iron absorption. Inclusion of foods rich in vitamin C in the diet of infants has been suggested as a possible means of increasing GI iron absorption.109,133

Chloramphenicol

Response to iron therapy may be delayed in patients receiving chloramphenicol. Therefore, chloramphenicol therapy should be avoided, if possible, in patients with iron-deficiency anemia receiving iron therapy.

Penicillamine

Orally administered iron decreases the cupruretic effect of penicillamine, probably by decreasing its absorption. Therefore, at least 2 hours should elapse between administration of penicillamine and iron.

Laboratory Test Interferences

Iron preparations color the feces black, and large amounts may interfere with tests used for detection of occult blood in the stools. The guaiac test occasionally yields false-positive tests for blood, whereas results with the benzidine test are not likely to be affected by iron medication.

Acute Toxicity

Pathogenesis

Following acute overdosage, most iron preparations are probably equally toxic per unit of elemental iron. Some studies in animals suggest that carbonyl iron may be less toxic than iron salts because of the mechanism of absorption of carbonyl iron, but comparative studies between these formulations in humans generally are lacking.148 The acute lethal dose of elemental iron in humans is estimated to be 180-300 mg/kg. However, a dose of elemental iron as low as 30 mg/kg may be toxic in some individuals, and ingestion of doses as low as 60 mg/kg have resulted in death.108

Iron is the most common cause of pediatric poisoning deaths reported to US poison control centers.108 In 1991, there were 5144 cases of accidental ingestion of oral iron preparations reported; 11 of these were fatal.108 Although many reported fatalities in children have been associated with accidental ingestion of 30 or more tablets of an oral iron preparation containing 60 mg of elemental iron per tablet (total dose 1.8 g or more of elemental iron), ingestion of as few as 5 or 6 tablets of a high-potency preparation could be fatal for a 10-kg child.108 Serious toxicity and/or death have occurred after accidental ingestion of oral iron preparations as well as multivitamin preparations (including prenatal vitamins) containing iron.108

Toxicity occurring with acute iron overdosage results from a combination of the corrosive effects on the GI mucosa and the metabolic and hemodynamic effects caused by the presence of excessive elemental iron.

Manifestations

The clinical course of acute iron poisoning has 4 distinct phases. Signs and symptoms may occur within 10-60 minutes or may be delayed several hours.

During the first phase, which may last 6-8 hours after ingestion, the patient experiences acute GI irritation including epigastric pain, nausea, vomiting, diarrhea of green and subsequently tarry stools, melena, and hematemesis which may be associated with drowsiness, pallor, cyanosis, lassitude, seizures, shock, and coma. Local erosion of the stomach and small intestine may result in increased iron absorption.

If death does not occur during the first phase, there may be a transient period of apparent recovery which may last up to 24 hours after ingestion (second phase). CNS abnormalities, metabolic acidosis, hepatic dysfunction or necrosis, renal failure, and bleeding diathesis occur during the third phase from 4-48 hours after ingestion and may progress to cardiovascular collapse, coma, and death.

Late complications of iron intoxication (fourth phase) occurring 2-6 weeks after overdosage include intestinal obstruction, pyloric stenosis, hepatic cirrhosis, or severe gastric scarring.

Treatment

Careful assessment of the severity of acute iron poisoning (the patient's clinical status, based on the estimated amount of iron ingested, abdominal radiographs, and measurement of serum iron concentrations and iron binding capacity) is necessary to determine appropriate management of the patient and to avoid unnecessary treatment. Patients who develop vomiting, diarrhea, leukocytosis (leukocyte count exceeding 15,000/mm³), hyperglycemia (blood glucose concentration exceeding 150 mg/dL), and/or an abdominal radiograph positive for iron within 6 hours of iron ingestion are likely to have a serum iron concentration exceeding 300 mcg/dL and to be at risk of serious toxicity, while those who do not develop any of these signs are unlikely to have a serum iron concentration exceeding 300 mcg/dL or to be at risk of toxicity requiring treatment. A negative deferoxamine challenge (see Deferoxamine Mesylate 64:00) or iron screening test obtained within 2 hours of ingestion also indicates that the patient has not ingested a clinically important amount of iron and probably does not require further assessment or treatment.

If ingestion exceeding 10 mg/kg of elemental iron has occurred within the previous 4 hours, the stomach should be emptied immediately by ipecac-induced emesis or, preferably, by lavage with a large bore tube. If the patient has had multiple episodes of vomiting, and especially if the vomitus contains blood, ipecac syrup should not be administered. Gastric lavage should be performed with tepid water or 1-5% sodium bicarbonate solution. Gastric lavage with disodium phosphate solution has also been used; however, administration of large volumes of this lavage solution has produced life-threatening hyperphosphatemia and hypocalcemia in some children. Although some clinicians suggest that use of sodium bicarbonate solution for gastric lavage generally appears to have no advantage compared with water for the treatment of iron overdose, the value of sodium bicarbonate solution in reducing iron absorption via formation of insoluble iron complexes remains to be established. Deferoxamine has also been used as an additive to gastric lavage solutions to chelate elemental iron in the GI tract; however, the efficacy of this procedure has not been clearly established. (See Deferoxamine Mesylate 64:00.) The possibility that gastric lavage may not remove enteric-coated and/or extended-release preparations should be considered. Whole gut lavage with 0.9% sodium chloride solution, administration of a saline cathartic, or surgical removal of iron tablets (which are visible in abdominal radiographs) may be required if other methods of removing the drug are unsuccessful. Hemodialysis is of little value in the treatment of iron intoxication.

When a potentially lethal dose of iron (180-300 mg/kg or more of elemental iron) has been ingested, serum iron concentrations exceed 400-500 mcg/dL or serum iron concentrations exceed total iron binding capacity, and/or the patient has severe symptoms of iron intoxication such as coma, shock, or seizures, chelation therapy with deferoxamine should be initiated. (See Deferoxamine Mesylate 64:00.) Supportive treatment including suction and maintenance of airway, correction of acidosis, and control of shock and dehydration with IV fluids or blood, oxygen, and vasopressors should be administered as required.

Pharmacology

Iron is present in all cells and has several vital functions. Ionic iron is a component of a number of enzymes necessary for energy transfer (e.g., cytochrome oxidase, xanthine oxidase, succinic dehydrogenase) and is also present in compounds necessary for transport and utilization of oxygen (e.g., hemoglobin, myoglobin). Cytochromes serve as a transport medium for electrons within cells. Hemoglobin is a carrier of oxygen from the lungs to tissues and myoglobin facilitates oxygen use and storage in muscle. Iron deficiency can interfere with these vital functions and lead to morbidity and mortality.

Administration of iron preparations corrects erythropoietic abnormalities caused by a deficiency of iron. Iron does not stimulate erythropoiesis nor does it correct hemoglobin disturbances not caused by iron deficiency. Administration of iron also relieves other manifestations of iron deficiency such as soreness of the tongue, dysphagia, dystrophy of the nails and skin, and fissuring of the angles of the lips.

Iron is vital for microorganisms such as bacteria, and the mineral plays a role both in bacterial pathogenicity and in host defense mechanisms.134 (See Cautions: Hemosiderosis.)

Pharmacokinetics

Absorption

Regulation of iron balance occurs mainly in the GI tract through absorption.109,110 When GI absorption is normal, functional iron is maintained and there is a tendency to establish iron stores.109,110,133

Absorption of iron is complex and is influenced by many factors including the form in which it is administered, the dose, iron stores, the degree of erythropoiesis, and diet. Oral bioavailability of iron can vary from less than 1% to greater than 50%,109,110 and the principal factor controlling GI iron absorption is the amount of iron stored in the body.109,111 GI absorption of iron increases when body iron stores are low and decreases when stores are sufficient or large.109,111 Increased erythrocyte production also can stimulate GI absorption of iron by severalfold.109,111

Approximately 5-13% of dietary iron is absorbed in healthy individuals and about 10-30% in iron-deficient individuals. Among adults, dietary iron absorption averages approximately 6% for males and 13% for nonpregnant females of childbearing potential; the higher GI absorption efficiency in these women principally results from lower body stores secondary to menstruation and pregnancy.109,110,112 GI absorption of iron increases during pregnancy to compensate for tissue growth and blood loss at delivery and postpartum, but the extent of this increase is not well defined;109,112 as iron stores become replenished postpartum, GI iron absorption decreases.109 GI iron absorption also is increased in iron-deficient individuals.109 As much as 60% of a therapeutic dose of an iron salt may be absorbed in iron-deficient patients; however, absorption of inorganic iron is decreased when it is administered with many foods and with some drugs. (See Drug Interactions.)

Inorganic iron reportedly is absorbed up to twice as well as dietary iron. Although the precise form in which iron is absorbed has not been elucidated, ferrous iron appears to be most readily absorbed. Oral bioavailability of iron also depends on dietary composition.109,110 Heme iron, which is present in meat, poultry, and fish, is absorbed 2-3 times more readily than non-heme iron, which is present in plant-based and iron-fortified foods.109,110 GI absorption of iron can be enhanced by dietary heme iron and vitamin C and can be inhibited by polyphenols (e.g., from certain vegetables), tannins (e.g., from tea), phytates (e.g., from bran), and calcium (e.g., from dairy products).109,111,113,133 Vegetarian diets are low in heme iron, but iron bioavailability can be increased by including other sources of iron and enhancers of GI iron absorption.109 Prior to the introduction of solid foods into the diet, the amount of iron absorbed in infants depends on the amount of iron present in breast milk or formula.109,133

Although absorption of iron can occur along the entire length of the GI tract, it is greatest in the duodenum and proximal jejunum and becomes progressively less distally. Enteric-coated and some extended-release preparations may transport iron past the duodenum and proximal jejunum, thus reducing iron absorption.

Following oral administration, carbonyl iron is dissolved in gastric secretions (i.e., hydrochloric acid) and converted to the hydrochloride salt prior to absorption from the stomach.148 The rate of absorption is affected by gastric acid production and the equilibrium between the formation of ionized iron and passage of the ionized iron to the intestine.148 Also affecting absorption is the particle size of carbonyl iron; a smaller particle size will be ionized more rapidly and thus absorbed more rapidly than formulations with a larger particle size.148

The mechanisms involved in iron absorption have not been completely elucidated; however, two mechanisms, which are believed to operate simultaneously, appear to be involved. An active transport process with enzymatic or carrier characteristics occurs principally with normal dietary concentrations of iron; a first-order passive transport process occurs principally with doses of iron exceeding those in a normal diet.

Distribution

Ferrous iron passes through GI mucosal cells directly into the blood and is immediately bound to transferrin. Transferrin, a glycoprotein β₁-globulin, transports iron to the bone marrow where it is incorporated into hemoglobin. When sufficient iron is present to meet the body's needs, most iron (greater than 70%) in the body is present as functional iron, with greater than 80% of functional iron existing in erythrocytes as hemoglobin and the rest existing in myoglobin and intracellular respiratory enzymes (e.g., cytochromes);109,111,133 less than 1% of total body iron is present in enzymes.133 The remainder of body iron is present as storage or transport iron.109,111,133 Total body iron is determined by intake, loss, and storage of the mineral.109,111,133

Small excesses of iron within the villous epithelial cells are oxidized to the ferric state. Ferric iron combines with the protein apoferritin to yield ferritin and is stored in mucosal cells, which are exfoliated at the end of their life span and excreted in the feces. Ferritin, a soluble protein complex, is the principal storage form of iron (about 70% in men and 80% in women), with smaller amounts being stored in hemosiderin, an insoluble protein complex.109,111 Ferritin and hemosiderin are present principally in the liver, reticuloendothelial system, bone marrow, spleen, and skeletal muscle; small amounts of ferritin also circulate in plasma.109,111 When long-term negative iron balance occurs, iron stores are depleted before hemoglobin concentration is reduced or iron deficiency ensues.109 In women, the iron storage reserve tends to be substantially less than that in men (about 0.2-0.4 g versus 1-4 g of iron), and is even less in children. Total body iron in full-term infants with normal or high birthweight is relatively high (averaging 75 mg/kg), to which iron stores contribute about 25%.109,133 Premature or low-birthweight infants are born with the same ratio of total body iron to body weight, but the amount of stored iron is low because of low body weight.109

The body of a healthy adult man contains approximately 3.8 g total or 50 mg/kg; that of an adult woman contains about 2.3 g total or 35-42 mg/kg. Iron exists in humans almost exclusively complexed to protein or in heme molecules. Approximately 70% is in hemoglobin, 25% in iron stores as ferritin and hemosiderin, 4% in myoglobin, 0.5% in heme enzymes, and 0.1% in transferrin. Erythrocyte formation and destruction is responsible for most iron turnover in the body.109 In adult males, about 95% of the iron required for erythropoiesis is recycled from the breakdown of erythrocytes and only 5% comes from oral intake.109 In infants, about 70% of iron required for erythropoiesis is recycled from the breakdown of erythrocytes and about 30% from oral intake.109

About 0.15-0.3 mg of iron is distributed into milk daily.

Transfer of iron across the placenta is believed to be an active process since it occurs against a concentration gradient. The total iron requirement for pregnancy may be 440 mg to 1.05 g.

Elimination

Iron metabolism occurs in a virtually closed system. Most of the iron liberated by destruction of hemoglobin is conserved and reused by the body. Daily excretion of iron in healthy men amounts to only 0.5-2 mg. This excretion occurs principally through feces and as desquamation of cells such as skin, GI mucosa, nails, and hair; only trace amounts of iron are excreted in bile and sweat.

Blood loss greatly increases iron loss. The average monthly loss of iron in normal menstruation is 12-30 mg, increasing the average iron requirement by 0.3-0.5 mg daily to compensate for this loss. The increased requirement secondary to pregnancy-associated tissue growth and blood loss at delivery and postpartum averages 3 mg daily over 280 days of gestation.109 In healthy individuals, trace amounts of blood are lost through physiologic GI loss109,133 secondary to normal turnover of intestinal mucosa.133 Pathologic GI blood loss occurs in infants and children sensitive to cow's milk109,133 and in adults secondary to peptic ulcer disease, inflammatory bowel syndrome, and GI cancer.109,133 Hookworm infections also are associated with blood loss.109,114,133

Chemistry and Stability

Chemistry

Ferrous fumarate, ferrous gluconate, ferrous sulfate, carbonyl iron, and polysaccharide-iron complex are commercially available in the US for oral administration in the prevention and treatment of iron deficiency. Ferric pyrophosphate and ferrous carbonate are available only as components of combination products.

Ferrous Fumarate

Ferrous fumarate occurs as a reddish-orange to red-brown, odorless powder. It may contain soft lumps that produce a yellow streak when crushed. The drug is slightly soluble in water and very slightly soluble in alcohol.

Ferrous Gluconate

Ferrous gluconate occurs as a yellowish-gray or pale greenish-yellow fine powder or granules with a slight odor of burned sugar. The drug is soluble in water with slight heating and practically insoluble in alcohol.

Ferrous Sulfate

Ferrous sulfate occurs as pale bluish-green, odorless crystals or granules which have a saline, styptic taste. The drug is efflorescent in dry air. Ferrous sulfate is freely soluble in water and insoluble in alcohol. Dried ferrous sulfate, which contains 86-89% anhydrous ferrous sulfate, occurs as a grayish-white to buff-colored powder which dissolves slowly in water and is insoluble in alcohol. Ferrous sulfate contains 7 molecules of water of hydration; dried ferrous sulfate consists mainly of the monohydrate with varying amounts of the tetrahydrate.

Carbonyl Iron

Carbonyl iron consists of microparticles of elemental iron; it is not an iron salt.148,190,191 Carbonyl iron is produced by a manufacturing process involving the controlled heating of vaporized iron pentacarbonyl, which is designed to result in the deposition of unchanged elemental iron as microscopic spheres of less than 5 µm in diameter.189,190 Carbonyl iron prepared for pharmaceutical or nutritional use in the US reportedly has an average particle size of 5-6 µm.148

Polysaccharide-Iron Complex

Polysaccharide-iron complex occurs as an amorphous brown powder and is very soluble in water and insoluble in alcohol.

Stability

Ferrous Sulfate

In moist air, ferrous sulfate rapidly oxidizes and becomes coated with brownish-yellow ferric sulfate which must not be used medicinally. The rate of oxidation is increased by the addition of alkali or by exposure to light.

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