Oral ferrous iron salts are the most economical and effective medication for the treatment of iron deficiency anemia. Of the various iron salts available, ferrous sulfate is the one most commonly used.
Although the traditional dosage of ferrous sulfate is 325 mg (65 mg of elemental iron) orally three times a day, lower doses (eg, 15-20 mg of elemental iron daily) may be as effective and cause fewer side effects. To promote absorption, patients should avoid tea and coffee and may take vitamin C (500 units) with the iron pill once daily. [18] However, a randomized trial in 140 adult patients with iron deficiency anemia found that oral iron taken alone and oral iron taken with 200 mg of vitamin C produced equivalent increases in hemoglobin and serum ferritin levels and equivalent rates of adverse events. [19]
However, a study by Moretti et al suggests that the standard dosing of iron supplements may be counterproductive. Their research focuses on the role of hepcidin, which regulates systemic iron balance, partly in response to plasma iron levels. They found that when a large oral dose of iron is taken in the morning, the resulting increase in the plasma iron level stimulates an increase in hepcidin, which in turn will interfere with the absorption of an iron dose taken later in the day; indeed, suppression of iron absorption could last as long as 48 hours. [20, 21]
In one part of their study, twice-daily doses of 60 mg or greater resulted in an increase in serum hepcidin levels after the first dose and a 35-45% decrease in the amount of iron that was absorbed from the second dose. With increasing doses, study subjects showed an increase in the absolute amount of iron absorbed, but a decrease in the fraction of the dose that was absorbed. A six-fold increase in iron dose (from 40 mg to 240 mg) resulted in only a three-fold increase in iron absorbed. In another part of the study, total iron absorbed from a morning and an afternoon dose on one day plus a morning dose the next day was not significantly greater than absorption from two consecutive morning doses. [20]
Moretti et al concluded that providing lower dosages and avoiding twice-daily dosing will maximize fractional iron absorption, and that their results support supplementation with 40-80 mg of iron taken every other day. A possible additional benefit of this schedule may be that improving absorption will reduce gastrointestinal exposure to unabsorbed iron and thereby reduce adverse effects from supplements. [20, 21] A subsequent longer-term study confirmed that in iron-depleted women, taking iron supplements daily in divided doses increases serum hepcidin and reduces iron absorption, whereas taking iron supplements on alternate days and in single doses optimizes iron absorption. [22]
Stoffel et al also concluded that alternate-day dosing of oral iron supplements may be preferable because it sharply increases fractional iron absorption. In their study, conducted in 19 women with iron deficiency anemia, total iron absorption from a single 200-mg dose given on alternate days was approximately twice that from 100 mg given on consecutive days (P < 0.001). [23]
Claims are made that other iron salts (eg, ferrous gluconate) are absorbed better than ferrous sulfate and have less morbidity. Generally, the toxicity is proportional to the amount of iron available for absorption. If the quantity of iron in the test dose is decreased, the percentage of the test dose absorbed is increased, but the quantity of iron absorbed is diminished.
Ferric citrate (Auryxia) gained US Food and Drug Administration (FDA) approval in November 2017 for treatment of iron deficiency anemia in adults with chronic kidney disease (CKD) who are not on dialysis. Each tablet of ferric citrate 1 gram is equivalent to 210 mg of ferric iron.
Approval was based on results from a 24-week placebo-controlled phase 3 clinical trial in 234 adults with stage 3-5 non–dialysis-dependent CKD. Trial participants had hemoglobin levels of 9-11.5 g/dL and were intolerant to or had an inadequate response to prior treatment with oral iron supplements. The starting dose in the study was 3 tablets daily with meals; the mean dose was 5 tablets per day. Importantly, during the study, patients were not allowed to receive any intravenous or oral iron, or erythropoiesis-stimulating agents (ESAs). Significant increases in hemoglobin levels of > 1 g/dL at any point during the 16-week efficacy period occurred in 52.1% of patients taking ferric citrate compared with 19.1% in the placebo group). [24]
Some authors advocate the use of carbonyl iron because of the greater safety for children who ingest their mothers’ medication. Decreased gastric toxicity is claimed but not clearly demonstrated in human trials. Bioavailability is approximately 70% of a similar dose of ferrous sulfate.
In July 2019, the FDA approved ferric maltol (Accrufer) for treatment of iron deficiency anemia in adults. Under the brand name Feraccru, ferric maltol is approved in the European Union for treatment in adults and in Switzerland for treatment in adults with inflammatory bowel disease (IBD). The FDA approval was based on 3 placebo-controlled trials (AEGIS 1 and 2 [IBD], AEGIS 3 [nondialysis CKD]). Ferric maltol improved Hb from baseline by 2.18 g/dL in AEGIS 1 and 2 and in AEGIS 3 by 0.52 g/dL. [25, 26]
Additionally, primary analysis from the phase IIIb AEGIS-H2H study showed oral ferric maltol to be noninferior to IV ferric carboxymaltose in patients with IBD. Further analysis and peer review of this study are in progress as of July 2019. Ferric maltol is an alternative to IV iron for patients that cannot tolerate salt-based oral iron therapies and wish to avoid parenteral treatment.
The usual benchmark for successful iron supplementation is a 2-g/dL increase in the hemoglobin (Hb) level in 3 weeks. [27] However, a meta-analysis of five randomized controlled trials concluded that in patients receiving oral iron supplementation, an Hb measurement on day 14 that shows an increase of 1.0 g/dL or more over baseline is an accurate predictor of longer-term and sustained response to continued oral therapy. The authors suggest that, "Day-14 Hb may be a useful tool for clinicians in determining whether and when to transition patients from oral to IV iron." [28]
Iron products that are administered parenterally include the following:
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Ferric carboxymaltose (Injectafer)
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Ferric derisomaltose (Monoferric)
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Ferric gluconate
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Ferric pyrophosphate citrate (Triferic)
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Ferumoxytol (Feraheme)
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Iron dextran complex
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Iron sucrose (Venofer)
Reserve parenteral iron for patients who are either unable to absorb oral iron or who have increasing anemia despite adequate doses of oral iron. It is expensive and has greater morbidity than iron preparations taken orally. Parenteral iron has been used safely and effectively in patients with IBD (eg, ulcerative colitis, Crohn disease), [29] in whom ferrous sulfate preparations may aggravate their intestinal inflammation.
In 2013, the FDA approved ferric carboxymaltose injection (Injectafer) for the intravenous (IV) treatment of iron deficiency anemia in adults who either cannot tolerate or have not responded well to oral iron. The drug is also indicated for the treatment of iron deficiency anemia in adults with non–dialysis-dependent CKD. Approval was based on two clinical studies in which the drug was given at a dose of 15 mg/kg body weight, up to a maximum of 750 mg, on two occasions at least 7 days apart, up to a maximum cumulative dose of 1500 mg of iron. [30, 31, 32]
A review of the safety of IV iron preparations, particularly in patients with CKD, by Kalra and Bhandari concluded that high molecular weight iron dextrans are associated with increased risks, so their use for IV therapy should be avoided. The second- and third-generation IV irons are considered equally efficacious in treating iron deficiency in equivalent doses, but iron isomaltoside seems to have a lower frequency of serious and severe hypersensitivity reactions. [33]
Feraheme (ferumoxytol injection), a hematinic, was initially approved by the FDA in 2009 to treat iron deficiency anemia in adults with CKD. Ferumoxytol injection consists of a superparamagnetic iron oxide that is coated with a carbohydrate shell, which helps isolate the bioactive iron from plasma components until the iron-carbohydrate complex enters the reticuloendothelial system macrophages of the liver, spleen, and bone. The released iron then either enters the intracellular storage iron pool (eg, ferritin) or is transferred to plasma transferrin for transport to erythroid precursor cells for incorporation into hemoglobin. [34]
In 2018, the FDA expanded the indication for ferumoxytol injection to include all eligible adults with iron deficiency anemia who have intolerance or unsatisfactory response to oral iron. Expanded approval was based on data from two phase 3 trials comparing ferumoxytol and iron sucrose, as well as data from a phase 3 trial comparing ferumoxytol with ferric carboxymaltose injection. In the phase 3 double-blind safety and efficacy study (n= 609) comparing ferumoxytol to iron sucrose, ferumoxytol treatment-emergent adverse events were mainly mild to moderate. Ferumoxytol was effective and well tolerated in patients with iron deficiency anemia of any underlying cause in whom oral iron was ineffective or could not be used. [35]
Ferric derisomaltose (Monoferric) was approved by the FDA in January 2020 for iron deficiency anemia in adults who have intolerance to oral iron or have had unsatisfactory response to oral iron. Efficacy was established in 2 clinical trials (n = 1550) that showed noninferiority of ferric derisomaltose compared with iron sucrose; the trials included patients with chronic renal impairment (estimated glomerular filtration rate [eGFR] 15-59 mL/min) and those receiving either no erythropoiesis-stimulating agents (ESAs) or ESAs at a stable dose. [36]
The safety of parenteral iron treatment was demonstrated in two trials that compared ferric derisomaltose with iron sucrose in 3050 patients with iron deficiency anemia: the FERWON-IDA trial, in patients with iron deficiency anemia, due to a broad variety of clinical diagnoses, and intolerance or lack of response to oral iron or a screening hemoglobin concentration sufficiently low to require rapid repletion of iron stores; and the FERWON‐NEPHRO trial, in patients with iron deficiency anemia due to non‐dialysis‐dependent CKD. Both trials achieved the co-primary safety endpoint, with a frequency of serious or severe hypersensitivity reactions of 0.3% during or after the first dose. In addition, the incidence rate of composite cardiovascular adverse events (hpertension, congestive heart failure, atrial fibrillation) was 2.5% in the ferric derisomaltose group and 4.1% in the iron sucrose group. [37]
Ferric pyrophosphate citrate (Triferic) is added to the bicarbonate concentrate of the hemodialysate to maintain hemoglobin in adult patients with hemodialysis-dependent CKD. It was approved by the FDA in 2015 as an iron replacement product in adult patients receiving long-term maintenance hemodisalysis. [38]