Ferrous Gluconate by JAMP Pharma Corporation

EFFECTIVE

• Anemia of chronic disease. Oral and intravenous (IV) iron in combination with erythropoiesis-stimulating agents (ESAs) are effective for treating anemia of chronic disease. Details: Iron supplementation with ESAs is effective for treating anemia associated with chronic kidney disease (CKD) or chemotherapy. During therapy with ESAs, iron levels should be monitored and supplementation provided as needed to ensure that the response is not limited by lack of iron for erythropoiesis (1087,1091,20110,20111,110192). Research shows that IV iron appears to be more effective than oral supplements for this purpose (20112,20113). In patients with CKD, IV iron at total doses from 2232 mg over 6 months to 1020 mg over one week increases hemoglobin levels more than oral doses of 4-6 mg/kg daily or 325 mg daily for up to 6 months (20112). Some research has evaluated the effect of IV or oral iron in patients not treated with ESAs. In patients with cancer or CKD, oral iron supplements have been shown to improve iron status (110184,110192). However, overall benefits of iron alone remain unclear in treated or untreated patients with cancer and more research is needed to rule out an increase in mortality and to determine any effect on blood transfusion requirements (110192). Preliminary clinical research shows that children aged 6 months to 10 years with HIV and anemia who take elemental iron 3 mg/kg daily along with a multivitamin for 3 months have a 41% lower chance of having persistent anemia at 3 months when compared with multivitamins alone (95432).
• Iron deficiency anemia. Oral and intravenous (IV) iron are effective for treating or preventing iron deficiency anemia. The benefits of iron supplementation in people with iron deficiency without anemia are unclear. Details: Oral iron supplements, mainly as ferrous sulfate, are effective for treating and preventing iron deficiency anemia in adults, children, and infants (1089,7135,17495,17496,17497,103806,20114,20115,91183,96621)(104680,104681,112601). Other forms are also effective, including sodium iron ethylenediaminetetra-acetate (NaFeEDTA), iron(III)-hydroxide polymaltose complex (IPC), iron protein succinylate, iron bisglycinate, and lactoferrin with iron (20117,20118,110189). Treatment with iron supplements should increase hemoglobin levels by 1 gram/dL every 2-3 weeks. However, even after hemoglobin has normalized, it may take up to 4 months for iron stores to be replenished (17497). Historically, treatment of iron deficiency anemia with oral iron supplements has typically consisted of a daily dosing regimen, often taken in divided doses to reduce adverse effects. In more recent years, however, intermittent iron supplementation (1-3 doses/week) has become preferred for some patients, particularly those with mild anemia, due to better absorption and a possible reduction in side effects compared to daily dosing. One small clinical study shows that taking ferrous sulfate 60 mg on alternate days in single doses improves iron absorption when compared to once daily dosing (96630). Another small clinical study in females with iron-deficiency anemia shows that fractional iron absorption is 40% to 50% higher with alternate-day dosing compared with daily dosing. Furthermore, total iron absorption was shown to be similar for alternate day dosing of elemental iron 200 mg compared with daily dosing of 100 mg, but the incidence of gastrointestinal adverse effects may be lower for the alternate day dosing regimen (101514). A meta-analysis of 25 clinical trials, including 10,996 menstruating females with or without pre-existing iron deficiency and/or anemia, shows that intermittent iron reduces the risk of anemia and increases hemoglobin and serum ferritin when compared with placebo or no intervention. This meta-analysis did not identify differences in the risk of anemia, hemoglobin, or serum ferritin between intermittent and daily iron supplementation. However, it did show that females receiving intermittent dosing had a 59% reduction in the risk for adverse effects. The validity of these findings is limited by significant heterogeneity in the enrolled populations and selected dosing strategies, including frequency of intermittent dosing, total weekly dose, and duration of follow-up. In addition, the subgroup analyses performed by baseline anemia, hemoglobin, and serum ferritin, as well as duration of follow-up, showed differing overall conclusions when comparing intermittent and daily iron supplementation. While intermittent dosing appears to be beneficial when compared with daily dosing for some patients with iron deficiency anemia, intermittent dosing may be less effective than daily iron supplementation in some patients (103806). For patients with severe anemia, twice daily dosing may be preferred to alternate day dosing due to faster response. A small clinical study in patients with iron deficiency anemia shows that taking ferrous sulfate 200 mg twice daily is more effective at increasing hemoglobin levels by 3 weeks when compared with ferrous sulfate 400 mg taken on alternate days in single doses (102864). Intermittent iron supplementation has also been investigated in children. A meta-analysis of clinical research in children and adolescents with or without pre-existing iron deficiency and/or anemia shows that taking iron supplements 1-2 times weekly is similarly effective as 3-7 times weekly for decreasing iron deficiency and iron deficiency anemia. However, ferritin and hemoglobin levels increased to a greater extent with 3-7 times weekly supplementation (112601). Blood transfusion may be required for some patients with severe iron deficiency anemia who have symptoms such as dyspnea and fatigue (17497). Intravenous iron should be considered in patients who cannot tolerate oral iron or in patients with chronic bleeding or intestinal malabsorption (17497). Guidance from the American Gastroenterological Association and the British Society of Gastroenterology recommends treatment with iron while awaiting investigations to rule out gastrointestinal issues in adults in the absence of an alternative explanation. Ferrous sulfate, fumarate, or gluconate daily are recommended. If adverse effects occur, intake can be reduced to once every other day, or alternative oral or parenteral sources of iron can be used. Parenteral sources should be used if oral sources are contraindicated or ineffective. Treatment should be monitored and continued after hemoglobin levels have normalized (110193,115890). Iron supplementation may also be beneficial in patients with iron deficiency without anemia, which can cause fatigue and reduced well-being, although guidelines are lacking. A meta-analysis of randomized controlled trials in adults with iron deficiency but not anemia shows that supplemental iron improves iron stores and hemoglobin levels. In addition, iron moderately reduces self-reported fatigue, but not physical capacity, when compared with placebo. Oral ferrous sulfate was used in most studies included in the analysis; however, IV or intramuscular iron were also used (104684). Intravenous iron has also been evaluated for the prevention of postoperative anemia. A meta-analysis of several, moderate-quality clinical studies in adults undergoing cardiac surgery, including patients with or without anemia, shows that various types of IV iron (e.g. ferric carboxymaltose, iron sucrose) reduce the risk of red blood cell transfusions by approximately 23%, and improve hemoglobin and iron levels by postoperative day 4, when compared with placebo and oral iron therapy (115898). The validity of these results is limited by heterogeneous methods across clinical studies including patient population, iron formulation, and use of erythropoietin.
• Pregnancy-related iron deficiency. Oral and intravenous (IV) iron are effective for managing pregnancy-related iron deficiency. Details: Clinical research shows that taking iron orally at an average daily dose of 15-225 mg of elemental iron increases maternal hemoglobin levels by up to 1 gram/dL when compared with placebo and reduces the risk of maternal anemia by 50% to 100% (20122,20123,20124,110180,110188,115895). Some clinicians may recommend alternating days of iron administration to reduce gastrointestinal adverse effects. A pooled analysis shows that taking iron supplements, with or without folic acid, on alternating days during pregnancy maintains adequate iron intake and reduces gastrointestinal adverse effects when compared with taking iron daily (96625). Another meta-analysis shows that daily supplementation of iron with folic acid increases hemoglobin levels by 0.24 g/dL when compared with intermittent supplementation, given as 1, 2, or 3 doses weekly. However, clinical significance of this slight increase is unlikely, and no difference in rates of anemia are noted between dosing strategies (115896). Various forms of oral iron seem to be equally effective for raising hemoglobin levels (110185,110188,115895). However, in patients with anemia during pregnancy, meta-analyses of several, moderate-quality clinical studies show that IV iron (e.g. iron sucrose) is more effective than oral iron (e.g. ferrous sulfate) for improving hemoglobin levels and reducing the risk for anemia (110185,115897).

POSSIBLY EFFECTIVE

• Breath-holding attacks. Oral iron seems to be effective for reducing the frequency of breath-holding attacks in children with iron deficiency. Details: The incidence of breath-holding attacks is increased in children with iron deficiency or iron deficiency anemia. Most research shows that oral supplementation with ferrous sulfate 3-6 mg/kg daily for 4-16 weeks reduces the frequency of breath-holding attacks in children aged 1-72 months (20128,104682,104683). The best evidence comes from a meta-analysis of one randomized controlled trial and 11 observational single arm studies (104682). In this analysis, approximately 84% of children experienced at least a 50% decreased frequency of breath-holding attacks (104682). Some preliminary clinical research also shows that administering intramuscular iron reduces the frequency of breath-holding attacks and increases remission in children with iron deficiency anemia (20128).
• Cognitive function. Oral iron seems to be effective for improving cognitive function in children and adolescents with iron deficiency. Details: Taking iron orally seems to improve cognitive function in iron-deficient children and adolescents (20121,112600). For example, ferrous sulfate 650 mg twice daily for 8 weeks improved verbal learning and memory in non-anemic iron-deficient adolescent females (1095). Ferrous sulfate 50 mg twice weekly for 16 weeks appeared to improve attention measures in adolescent females with possible anemia (91186). Iron also appears to reverse developmental and learning deficits caused by iron-deficiency in anemic infants (1104). Some clinical research is focused on children and adolescents from low- and middle-income countries. In children aged 5-19 years with or without iron-deficiency anemia, a meta-analysis of clinical research shows that iron supplementation for 3-8 months dose-dependently improves measured intelligence by a modest amount. However, there was no effect on other measures of cognition, including attention or memory (110181). Another meta-analysis of clinical research in school age children shows that taking iron for 2-12 months modestly improves intelligence, attention, and memory, but not educational achievement, when compared with placebo or no intervention. However, sub-analyses show that any benefits are limited to children with anemia (112600). Most studies included in the analyses evaluated daily iron supplementation, with a few studies assessing iron taken 4-6 times weekly (110181,112600). In contrast, a large clinical trial in schoolchildren in Ethiopia shows that taking iron supplements, providing 42 mg of elemental iron, once weekly for 11 months does not improve working memory, nonverbal intelligence, planning, or problem-solving, and may even worsen one measure of attention and concentration when compared with placebo (113904). These discrepant findings may be related to differences in frequency of dosing (daily vs. weekly) and baseline demographics; only 20% and 4% of children in this study had iron deficiency and iron deficiency anemia, respectively.
• Heart failure. Intravenous (IV) iron seems to be effective for improving certain outcomes in patients with heart failure and iron deficiency. It is unclear if oral iron is effective. Details: Iron deficiency is common in patients with heart failure (17499,112597,112598,112599). A number of large clinical trials and meta-analyses of clinical research in patients with heart failure show that administering IV iron, as ferric carboxymaltose, iron dextran, iron isomaltoside, or iron sucrose, for at least 12 weeks modestly improves quality of life, increases exercise capacity, and reduces hospitalizations when compared with placebo or standard care. However, there was no effect on all-cause mortality or cardiovascular mortality (17498,91179,110176,110187,112597,112598,112599,113900,113901). Based on these results, guidelines from the American Heart Association and European Society of Cardiology support the use of IV iron in patients with heart failure with reduced ejection fraction and iron deficiency to improve symptoms and quality of life. Additionally, IV iron supplementation in these patients is associated with a reduced risk of heart failure hospitalization (115935,115936). Limited research has investigated the effect of oral iron in this population. A small meta-analysis of clinical research shows with low certainty that taking iron orally has beneficial effects on serum ferritin and left ventricular ejection fraction (110178). Most research shows that taking oral iron does not improve hemoglobin levels, quality of life, or exercise capacity when compared with placebo (100970,110178). However, one small clinical trial shows that taking oral iron modestly improves iron status and overall symptoms and increases the 6-minute walking distance by about 46 meters, compared with a reduction of only 14 meters in those taking placebo (110183). Some doses used in individual clinical studies have included iron polysaccharide 150 mg twice daily for 16 weeks and ferrous sulfate 200 mg three times daily for 12 weeks (100970,110183).
• Restless legs syndrome (RLS). Oral and intravenous (IV) iron seem to be beneficial for RLS. The American Academy of Neurology recommends a combination of oral ferrous sulfate and vitamin C or IV ferric carboxymaltose for patients with RLS. Details: RLS is commonly associated with iron deficiency anemia. Some clinical research shows that taking iron in the form of ferrous sulfate 325 mg twice daily for 12 weeks reduces RLS symptoms comparably to pramipexole. Symptoms such as leg discomfort, need to move, and sleep disturbances improved considerably in about half of the patients taking either treatment (91181). Additional clinical research shows that taking ferrous sulfate 325 mg twice daily along with vitamin C 100 mg twice daily for 12 weeks reduces symptoms of RLS when compared with vitamin C alone in patients with RLS and low-normal serum ferritin levels (94189). Based on these results, clinical practice guidelines by the American Academy of Neurology report that taking this combination of oral ferrous sulfate and vitamin C is likely to improve symptoms in patients with RLS and low-normal serum ferritin (93587). Intravenous iron may also reduce symptoms of RLS. Clinical practice guidelines by the American Academy of Neurology report that two doses of IV ferric carboxymaltose 500 mg given 5 days apart are likely to improve symptoms and quality of life within 28 days in patients with moderate to severe RLS, regardless of serum ferritin levels. Iron sucrose, given IV, has also been evaluated in patients with RLS, but there is currently insufficient available evidence to support or refute the use of this form of iron for treating RLS (93587). Additionally, IV and oral iron have been compared in the management of RLS. A clinical study in adults with RLS and iron deficiency anemia shows that administering IV ferumoxytol 1020 mg for 2 doses, 2-7 days apart, reduces self-reported symptom severity and frequency comparably to taking oral ferrous sulfate 650 mg daily for 6 weeks (115894). The validity of these results is limited by methodological concerns, including lack of a placebo control group and failure to obtain all follow-up data.

POSSIBLY INEFFECTIVE

• Athletic performance. Oral iron does not seem to improve athletic performance. Details: A meta-analysis of clinical research in adults of childbearing age shows that iron supplementation improves some exercise performance measures, such as maximal oxygen uptake capacity, but not others, such as time until exhaustion and energy consumption, when compared with control (91184). Another meta-analysis of clinical research in patients with iron deficiency without anemia shows that iron supplementation improves subjective measures of fatigue, but does not improve exercise time to exhaustion or other measures of physical capacity (104684). A small clinical study in healthy children shows that taking iron supplements or consuming food providing iron 30-200 mg daily for 1-2 months improves running performance when compared with placebo. This was demonstrated by reductions of heart rate of 6.6 to 8 beats per minute during the running exercise. One preliminary study included in this analysis also showed that iron supplementation improved treadmill endurance time (20140).
• Child growth. Oral iron does not seem to be beneficial for child growth. Details: Meta-analyses of mainly preliminary clinical research show that oral iron supplementation, at doses averaging 2-80 mg or 1-10 mg/kg elemental iron daily for up to 52 weeks, does not increase growth rate in children (20131,20132,20133,95434).
• Preterm labor. Oral iron does not seem to prevent preterm labor and may actually increase the risk in malaria-endemic regions. Details: A meta-analysis of results from five clinical studies shows that maternal intake of iron as ferrous sulfate 20-60 mg daily for 14-26 weeks starting in the second trimester of pregnancy does not affect the length of gestation or increase birthweight of the infant (95434). In females from a malaria-endemic area who have never been pregnant before, another clinical study shows that taking ferrous gluconate 60 mg and folic acid 2.8 mg weekly, starting before conception and continuing to the first antenatal visit, may more than double the risk of preterm birth, defined as a delivery under 37 weeks gestation, when compared with folic acid alone (100969). Some research suggests that the adverse outcome in this latter study may be explained by a rise in hepcidin levels in pregnant patients with malaria. Hepcidin is a hormone that regulates iron absorption and distribution, and malaria can upregulate hepcidin. High levels of hepcidin can decrease iron absorption, stimulate inflammatory processes, and cause progesterone withdrawal, leading to preterm labor (102863).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• ACE inhibitor-induced cough. It is unclear if oral iron is beneficial in patients with this condition. Details: A small clinical trial shows that taking ferrous sulfate 256 mg daily reduces or eliminates cough induced by ACE inhibitors such as captopril (Capoten), enalapril (Vasotec), lisinopril (Prinivil, Zestril), and others, when compared with placebo (7307).
• Androgenic alopecia. Oral iron has only been evaluated in combination with other ingredients, its effect when used alone is unclear. Details: A moderate-sized clinical study in adults with androgenic alopecia or telogen effluvium shows that taking one tablet daily of a specific product (GFM Oral, Cantabria Labs), providing an unknown dose of iron in combination with selenium, taurine, cysteine, methionine, and hydrolyzed collagen, along with conventional therapy, consisting primarily of finasteride or minoxidil, for 12 weeks improves hair loss when compared with conventional therapy alone (111636). It is unclear if this effect is due to iron, other ingredients, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral iron is beneficial in children with ADHD. Details: A meta-analysis of three small, lower quality clinical studies in children and adolescents with ADHD and iron deficiency shows that taking ferrous fumarate 200-400 mg, dependent upon body weight, or ferrous sulfate 80 mg daily for 3 months does not improve hyperactivity and inattention when compared with placebo. However, the results of individual clinical studies are inconsistent (115893). The validity of these results is limited by high heterogeneity across clinical studies, including patient baseline characteristics, use of investigator-, parent-, and teacher-rated ADHD scales, and concomitant use of ADHD medication therapy (e.g. stimulants).
• Child development. It is unclear if oral iron is beneficial for improving development in non-anemic children. Details: Some observational research has found that iron deficiency in infancy is associated with poor verbal performance and social skills in childhood (102862). It is unknown whether iron supplementation can ameliorate these developmental issues. In non-anemic infants and children, clinical research shows that iron does not improve cognitive performance; the evidence for the benefits of iron on psychomotor development is conflicting (20129,20130,91315,96616,96626,115891).
• Esophageal cancer. It is unclear if oral iron is beneficial for esophageal cancer prevention. Details: Population research has found that taking iron supplements is associated with a 32% lower risk of esophageal adenocarcinoma when compared to never taking iron supplements. However, use of iron supplements is not associated with a lower risk of esophageal squamous cell carcinoma (95435).
• Fatigue. It is unclear if oral iron is beneficial in patients with fatigue due to iron deficiency without anemia. Details: A meta-analysis of mainly preliminary clinical research in adults with iron deficiency without anemia shows that iron reduces self-reported fatigue moderately more than placebo (104684). A specific ferrous sulfate supplement (Tardyferon; Pierre Fabre Médicament) providing 80 mg of elemental iron daily for 4-12 weeks was used in two studies included in this analysis (11406,91188).
• Inflammatory bowel disease (IBD). In patients with active IBD, intravenous iron may be more beneficial than oral iron due to impaired absorption. However, it may also increase the risk of infection in these patients. Details: Since the absorption of oral iron may be impaired in patients with active symptoms of IBD, guidelines from the British Society of Gastroenterology suggest that treatment with parenteral iron may be needed in patients with IBD who have moderate to severe iron-deficiency anemia (110193). However, a meta-analysis of clinical research in this population shows that administering IV iron, usually as iron sucrose or ferric carboxymaltose, increases the risk of infection by 73% when compared with oral iron or no iron (110186).
• Postoperative recovery. It is unclear if intravenous (IV) iron is beneficial for recovery following cardiac surgery. Details: A meta-analysis of low- to moderate-quality clinical research in patients with preoperative iron-deficiency anemia shows that treatment with IV iron before cardiac surgery does not improve the rate of transfusions or the length of stay in the intensive care unit or hospital when compared with control groups, including placebo, oral iron, or no treatment. Also, a meta-analysis of clinical research shows that IV iron does not reduce postoperative mortality rates (110182).
• Postpartum depression. Although there has been interest in using iron for postpartum depression, there is insufficient reliable information about the clinical effects of iron for this condition.
• Prematurity. Enteral iron seems to be beneficial for some measures of development in preterm infants. Details: A meta-analysis of clinical research in preterm or low birthweight infants fed human milk shows that enteral iron supplementation increases linear growth and reduces the risk of anemia when compared with control groups receiving no iron supplementation. However, there was no effect on serum ferritin, weight, head circumference, cognitive development, risk of infection, or risk of necrotising enterocolitis (110177). Additional clinical research in infants born at 24-28 weeks' gestation shows that a higher average enteral iron dose by 60 days of age is positively associated with cognitive performance at 2 years of corrected age. However, this association was not present for iron doses received at 90 days of age (110190). More evidence is needed to rate iron for these uses.

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LIKELY SAFE ...when used orally and appropriately. For people age 14 and older with adequate iron stores, iron supplements are safe when used in doses below the tolerable upper intake level (UL) of 45 mg per day of elemental iron. The UL is not meant to apply to those who receive iron under medical supervision (7135,96621). To treat iron deficiency, most people can safely take up to 300 mg elemental iron per day (15). ...when used intravenously and appropriately. Ferric carboxymaltose 200 mg and iron sucrose 200 mg have been given intravenously for up to 10 doses with no reported serious adverse effects (91179). A meta-analysis of clinical studies of hemodialysis patients shows that administering high-dose intravenous (IV) iron does not increase the risk of hospitalization, infection, cardiovascular events, or death when compared with low-dose IV iron, oral iron, or no iron treatment (102861). A more recent meta-analysis of clinical studies of all patient populations shows that administering IV iron does not increase the risk of hospital length of stay or mortality, although the risk of infection is increased by 16% when compared with oral iron or no iron (110186). Another meta-analysis of 3 large clinical trials in patients with heart failure shows that IV ferric carboxymaltose at a dose of around 1500 mg every 6 months for a year does not increase the incidence of adverse effects when compared with placebo (113901). Despite these findings, there are rare reports of hypophosphatemia and/or osteomalacia (112603,112608,112609,112610,113905).

LIKELY UNSAFE ...when used orally in excessive doses. Doses of 30 mg/kg are associated with acute toxicity. Long-term use of high doses of iron can cause hemosiderosis and multiple organ damage. The estimated lethal dose of iron is 180-300 mg/kg; however, doses as low as 60 mg/kg have also been lethal (15).

CHILDREN: LIKELY SAFE
when used orally and appropriately (7135,91183,112601).

CHILDREN: LIKELY UNSAFE
when used orally in excessive amounts. Tell patients who are not iron-deficient not to use doses above the tolerable upper intake level (UL) of 40 mg per day of elemental iron for infants and children aged 0-13 years and 45 mg per day for children aged 14-18 years. Higher doses frequently cause gastrointestinal side effects such as constipation and nausea (7135,20097). Iron is the most common cause of pediatric poisoning deaths. Doses as low as 60 mg/kg can be fatal (15).

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately. Iron is safe during pregnancy and breast-feeding in patients with adequate iron stores when used in doses below the tolerable upper intake level (UL) of 45 mg daily of elemental iron (7135,96625,110180).

PREGNANCY AND LACTATION: LIKELY UNSAFE
when used orally in high doses. Tell patients who are not iron deficient to avoid exceeding the tolerable upper intake level (UL) of 45 mg daily of elemental iron. Higher doses frequently cause gastrointestinal side effects such as nausea and vomiting (7135) and might increase the risk of preterm labor (100969). High hemoglobin concentrations at the time of delivery are associated with adverse pregnancy outcomes (7135,20109).

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BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron reduces the absorption of bisphosphonates.  Details Advise patients that doses of bisphosphonates should be separated by at least two hours from doses of all other medications, including supplements such as iron. Divalent cations, including iron, can decrease absorption of bisphosphonates by forming insoluble complexes in the gastrointestinal tract (15).

CHLORAMPHENICOL Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, taking chloramphenicol with iron might reduce the response to iron therapy in iron deficiency anemia.  Details Chloramphenicol interferes with erythrocyte maturation (15,3046). However, since chloramphenicol isn't usually taken for prolonged periods, this isn't likely to be clinically significant.

DENOSUMAB (Prolia, others) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Administration of intravenous iron within one month of denosumab administration might increase the risk of severe hypophosphatemia and hypocalcemia.  Details A case of severe hypocalcemia (albumin corrected calcium 6.88 mg/dL, ionized calcium 3.68 mg/dL) and hypophosphatemia (<0.5 mg/dL) with respiratory acidosis, QT interval prolongation, and nonsustained ventricular tachycardia was reported in a 76-year-old male who had received an iron polymaltose infusion within 2 weeks of a subcutaneous injection of denosumab. Serum parathyroid hormone was also elevated (348 pg/mL). Subsequent iron infusions with iron polymaltose and ferric carboxymaltose were followed by transient hypophosphatemia, but without hypocalcemia. Additionally, a literature review describes 6 additional cases of hypophosphatemia and hypocalcemia in patients 52-92 years of age who had been administered intravenous iron as either ferric carboxymaltose or iron polymaltose and subcutaneous denosumab within 1-4 weeks of each other (113905).

DOLUTEGRAVIR (Tivicay) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease dolutegravir levels by reducing its absorption.  Details Advise patients to take dolutegravir at least 2 hours before or 6 hours after taking iron. Pharmacokinetic research shows that iron can decrease the absorption of dolutegravir from the gastrointestinal tract through chelation (93578). When taken under fasting conditions, a single dose of ferrous fumarate 324 mg orally along with dolutegravir 50 mg reduces overall exposure to dolutegravir by 54% (94190).

INTEGRASE INHIBITORS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, taking iron along with integrase inhibitors might decrease the levels and clinical effects of these drugs.  Details Iron is a divalent cation. There is concern that iron may decrease the absorption of integrase inhibitors from the gastrointestinal tract through chelation (93578). One pharmacokinetic study shows that iron can decrease blood levels of the specific integrase inhibitor dolutegravir through chelation (94190). Also, other pharmacokinetic research shows that other divalent cations such as calcium can decrease the absorption and levels of some integrase inhibitors through chelation (93578,93579).

LEVODOPA Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease levodopa levels by reducing its absorption.  Details Advise patients to separate doses of levodopa and iron as much as possible. There is some evidence in healthy people that iron forms chelates with levodopa, reducing the amount of levodopa absorbed by around 50% (9567). The clinical significance of this hasn't been determined.

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease levothyroxine levels by reducing its absorption.  Details Advise patients to separate levothyroxine and iron doses by at least 2 hours. Iron can decrease the absorption and efficacy of levothyroxine by forming insoluble complexes in the gastrointestinal tract (9568).

METHYLDOPA (Aldomet) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Iron might decrease methyldopa levels by reducing its absorption.  Details Advise patients to separate methyldopa and iron doses by at least 2 hours. Iron can decrease the absorption of methyldopa from the gastrointestinal tract through chelation, resulting in increases in blood pressure (7900,20151).

MYCOPHENOLATE MOFETIL (CellCept) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Unlikely •  Level of Evidence = D Theoretically, iron might decrease mycophenolate mofetil levels by reducing its absorption.  Details Advise patients to take iron 4-6 hours before, or 2 hours after, mycophenolate mofetil. It has been suggested that a decrease of absorption is possible, probably by forming nonabsorbable chelates. However, mycophenolate pharmacokinetics are not affected by iron supplementation in available clinical research (3046,20152,20153,20154,20155).

PENICILLAMINE (Cuprimine, Depen) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease penicillamine levels by reducing its absorption.  Details Advise patients to separate penicillamine and iron doses by at least 2 hours. Oral iron supplements can reduce absorption of penicillamine by 30% to 70%, probably due to chelate formation. In people with Wilson's disease, this interaction has led to reduced efficacy of penicillamine (3046,3072,20156).

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease levels of quinolone antibiotics by reducing their absorption.  Details Advise patients to separate quinolone antibiotics and iron doses by at least 2 hours. Iron decreases the absorption of quinolones due to formation of insoluble complexes in the gastrointestinal tract (15,3072).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Iron might decrease levels of tetracycline antibiotics by reducing their absorption.  Details Advise patients to take iron at least 2 hours before or 4 hours after tetracycline antibiotics. Concomitant use can decrease absorption of tetracycline antibiotics from the gastrointestinal tract by 50% to 90% (15).

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General ...Orally or intravenously, iron is generally well tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Abdominal pain, constipation, diarrhea, gastrointestinal irritation, nausea, and vomiting.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about oral or gastric ulcerations.
Intravenously: Case reports have raised concerns about hypophosphatemia and osteomalacia.

Cardiovascular ...There is debate regarding the association between coronary heart disease (CHD) or myocardial infarction (MI) and high iron intake or high body iron stores. Some observational studies have reported that high body iron stores are associated with increased risk of MI and CHD (1492,9542,9544,9545,15175). Some observational studies reported that only high heme iron intake from dietary sources such as red meat are associated with increased risk of MI and CHD (1492,9546,15174,15205,15206,91180). However, the majority of research has found no association between serum iron levels and cardiovascular disease (1097,1099,9543,9547,9548,9549,9550,56469,56683).
There is one case of Kounis syndrome, also referred to as allergic angina or allergic myocardial infarction, in a 39-year-old female patient without previous coronary artery disease given intravenous ferric carboxymaltose. The patient experienced anaphylactic symptoms, including headache, abdominal pain, and breathing difficulties, 3 minutes after starting the infusion. She was further diagnosed with non-ST-elevation myocardial infarction (112607).
There is also a case of a 56-year-old female, negative for HFE mutation homozygosity, diagnosed with acquired iron overload cardiomyopathy after starting ferrous sulfate 325 mg twice daily 3 years prior for iron deficiency secondary to alcoholic cirrhosis with esophageal varices and encephalopathy. The patient had no follow-up care over the 3 years and denied any blood transfusions over that time (113906).

Dermatologic ...Cutaneous hemosiderosis, or skin staining, has been reported following intravenous (IV) iron infusion in various case reports. Most of these cases are due to extravasation following iron infusion (112605,112611). In one case, extravasation has occurred following iron derisomaltose infusion in a 41-year-old female with chronic kidney disease (112605). Rarely, diffuse cutaneous hermosiderosis has occurred. In one case, a 31-year-old female with excessive sweating developed cutaneous hemosiderosis in the armpits following an (IV) iron polymaltose infusion (112611).

Endocrine ...Population research in females shows that higher ferritin levels are associated with an approximately 1. 5-fold higher odds of developing gestational diabetes. Increased dietary intake of heme-iron, but not non-heme iron, is also associated with an increased risk for gestational diabetes. The effects of iron supplementation could not be determined from the evaluated research (96618). However, in a sub-analysis of a large clinical trial in pregnant adults, daily supplementation with iron 100 mg from 14 weeks gestation until delivery did not affect the frequency or severity of glucose intolerance or gestational weight gain (96619).
Intravenous (IV) iron may trigger hypophosphatemia in some patients (113905). A meta-analysis of clinical studies in adults with iron deficiency anemia shows that IV ferric carboxymaltose is associated with a higher risk of hypophosphatemia when compared with other IV formulations (i.e. iron dextran, iron isomaltoside, iron sucrose, and ferumoxytol) (115899). Severe hypophosphatemia requiring IV phosphate has also occurred following IV ferric carboxymaltose (112608,112610).
Additionally, cases of osteomalacia related to hypophosphatemia subsequent to parenteral iron administration have been rarely reported (112603,112609).

Gastrointestinal ...Orally, iron can cause dry mouth, gastrointestinal irritation, heartburn, abdominal pain, constipation, diarrhea, nausea, or vomiting (96621,102864,104680,104684,110179,110185,110188,110189,110192,115894). These adverse effects are uncommon at doses below the tolerable upper intake level (UL) of 45 mg per day of elemental iron in adults with normal iron stores (7135). Higher doses can be taken safely in adults with iron deficiency, but gastrointestinal side effects may occur (1095,20118,20119,56698,102864). Taking iron supplements with food seems to reduce gastrointestinal side effects (7135). However, food can also significantly reduce iron absorption. Iron should be taken on an empty stomach, unless it cannot be tolerated.
There are several formulations of iron products such as ferrous sulfate, ferrous gluconate, ferrous fumarate, and others. Manufacturers of some formulations, such as polysaccharide-iron complex products (Niferex-150, etc), claim to be better tolerated than other formulations; however, there is no reliable evidence to support this claim. Gastrointestinal tolerability relates mostly to the elemental iron dose rather than the formulation (17500).
Enteric-coated or controlled-release iron formulations might reduce nausea for some patients, however, these products also have lower absorption rates (17500).
Liquid oral preparations can blacken and stain teeth (20118).
Iron can also cause oral ulcerations and ulcerations of the gastric mucosa (56684,91182,96622,110179). In one case report, an 87-year-old female with Alzheimer disease experienced a mucosal ulceration, possibly due to holding a crushed ferrous sulfate 80 mg tablet in the mouth for too long prior to swallowing (91182). The ulceration was resolved after discontinuing iron supplementation. In another case report, a 76-year old male suffered gastric mucosal injury after taking a ferrous sulfate tablet daily for 4 years (56684). In a third case report, a 14-year-old female developed gastritis involving symptoms of upper digestive hemorrhage, nausea, melena, and stomach pain. The hemorrhage was attributed to supplementation with ferrous sulfate 2 hours after meals for the prior 2 weeks (96622). In one case report, a 43-year old female developed atrophic gastritis with non-bleeding ulcerations five days after starting oral ferrous sulfate 325 mg twice daily (110179).
Intravenously, iron can cause gastrointestinal symptoms such as nausea and diarrhea(104684,110192,115894).

Hematologic ...Orally, iron supplements have been associated with hemochromatosis. In one case report, a 56-year-old female, negative for HFE mutation homozygosity, was diagnosed with acquired hemochromatosis after starting ferrous sulfate 325 mg twice daily 3 years prior, without follow-up care, for a previous iron deficiency secondary to alcoholic cirrhosis with esophageal varices and encephalopathy (113906).

Immunologic ...Although there is some clinical research associating iron supplementation with an increased rate of malaria infection (56796,95432), the strongest evidence to date does not support this association, at least for areas where antimalarial treatment is available (95433,96623). In an analysis of 14 trials, iron supplementation was not associated with an increased risk of malaria (96623). In a sub-analysis of 7 preliminary clinical studies, the effect of iron supplementation was dependent upon the access to services for antimalarial treatment. In areas where anemia is common and services are available, iron supplementation is associated with a 9% reduced risk of clinical malaria. In an area where services are unavailable, iron supplementation was associated with a 16% increased risk in malaria incidence (96623). The difference in these findings is likely associated with the use of malaria prevention methods.
A meta-analysis of clinical studies of all patient populations shows that administering intravenous (IV) iron, usually iron sucrose and ferric carboxymaltose, increases the risk of infection by 16% when compared with oral iron or no iron. However, sub-analyses suggest this increased risk is limited to patients with inflammatory bowel disease (IBD) (110186). Additionally, a meta-analysis in adults with cancer-associated anemia shows that IV iron does not increase the risk of infection when compared with oral iron or no iron therapy (115892).
Intravenously, iron has rarely resulted in allergic reactions, including anaphylactoid reactions (110185,110192,112606,112607). There is one case of Kounis syndrome, also referred to as allergic angina or allergic myocardial infarction, in a 39-year-old female patient without previous coronary artery disease given IV ferric carboxymaltose. The patient experienced anaphylactic symptoms, including headache, abdominal pain, and breathing difficulties, 3 minutes after starting the infusion. She was further diagnosed with non-ST-elevation myocardial infarction (112607).

Musculoskeletal ...Intravenous (IV) iron may trigger hypophosphatemia in some patients, and cases of osteomalacia related to hypophosphatemia subsequent to parenteral iron administration have been rarely reported (112609,113905). In one case, a 70-year-old male with a genetic hemorrhagic disorder infused with ferric carboxymaltose developed lower limb pain with hypophosphatemia and diffuse bone demineralization in the feet (112609). In a second case, a 61-year-old male developed femoral neck insufficiency fractures following repeated ferric carboxymaltose transfusions for anemia related to vascular malformation in the bowel (112603).

Oncologic ...There is a debate regarding the association between high levels of iron stores and cancer. Data are conflicting and inconclusive (1098,1099,1100,1102). Epidemiological studies suggest that increased body iron stores may increase the risk of cancer or general mortality (56703).
Occupational exposure to iron may be carcinogenic (56691). Oral exposure to iron may also be carcinogenic. Pooled analyses of population studies suggest that increasing the intake of heme iron increases the risk of colorectal cancer. For example, increasing heme iron intake by 1 mg/day is associated with an 11% increase in risk (56699,91185).

Pulmonary/Respiratory ...Orally, iron has been associated with rare reports of iron pill aspiration. This occurs when all or part of the pill is aspirated into the lungs. Once in the lungs, it can cause a chemical burn of the bronchial mucosa. Dozens of cases of iron pill aspiration have been reported in individuals ranging in age from 22 months to 92 years. Patients presented with cough, dyspnea, wheezing, and hemoptysis. The hemoptysis led to death in 2 patients due to hemorrhage. Long-term complication of fibrosis and bronchial stenosis was reported in a few of the cases. In one case, a 48-year-old female accidentally aspirated a ferrous sulfate tablet and presented to the emergency department with cough, blood-stained sputum, chest pain, dyspnea, and acute distress. Bronchoscopy was performed, parts of the pill were retrieved, and chemical burns and necrotic tissue were observed in the bronchus intermedius mucosa and throughout the middle and lower lobes. Debridement with bronchoalveolar lavage was performed. The patient was transferred to the intensive care unit, placed on mechanical ventilation for 2 days, treated with corticosteroids, and discharged on the fifth day of hospitalization. Four weeks post-discharge the patient had significantly improved but still had some reduction in lung capacity.

Other ...Intravenously, sodium ferric gluconate complex (SFGC) caused drug intolerance reactions in 0. 4% of hemodialysis patients including 2 patients with pruritus and one patient each with anaphylactoid reaction, hypotension, chills, back pain, dyspnea/chest pain, facial flushing, rash and cutaneous symptoms of porphyria (56527).

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