Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

all patients

1st line – oral iron replacement

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ACUTE
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all patients
1st line – 

oral iron replacement

Initial treatment is daily oral iron replacement therapy (e.g., ferrous sulfate, ferrous gluconate, or ferric maltol). Ferrous iron salts have better bioavailability and absorption compared with ferric iron salts.[121]

Oral iron supplementation administered as a single dose on alternate days (e.g., Monday, Wednesday, and Friday) may optimise iron absorption and offer more convenient dosing compared with daily oral iron supplementation.[122][123][124] Iron replacement therapy should continue after normalisation of hematological parameters to replenish bodily iron stores.

Up to 10% of patients may have gastrointestinal intolerance to oral iron. Alternative options for these patients include switching to a formulation with lower elemental iron per pill, taking a liquid formulation, taking pills with food (although this will decrease absorption), or switching to intravenous iron.

In women with twin pregnancy and IDA, doubling the dose of iron may provide benefit without causing gastrointestinal adverse effects. [176]

A full blood count and reticulocyte count should be monitored during treatment. The reticulocyte count should peak at 1 to 2 weeks; hemoglobin should show improvement at 3 to 4 weeks (by 2 g/dL) with normalisation of hemoglobin after 2 to 4 months, and replacement of iron stores after 6 months.[4]

Absorption of nonheme iron in plants and dairy requires acid for digestion. Absorption is enhanced by ascorbic acid (vitamin C) and meat, and inhibited by calcium, fibre, tea, coffee, and wine.[22]

Primary options

ferrous sulfate: children: 3-6 mg/kg/day orally given in 3 divided doses; adults: 50-100 mg orally three times daily

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OR

ferrous gluconate: children: 3-6 mg/kg/day orally given in 3 divided doses; adults: 50-100 mg orally three times daily

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OR

ferrous fumarate: children: 3-6 mg/kg/day orally given in 3 divided doses; adults: 50-100 mg orally three times daily

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OR

ferric maltol: adults: 30 mg orally twice daily

2nd line – intravenous iron replacement

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ACUTE
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all patients
2nd line – 

intravenous iron replacement

Patients not responding to oral iron or who are intolerant of oral iron can be considered for intravenous iron replacement. Results from an analysis of five trials suggest that patients should be transitioned from oral iron to intravenous iron if hemoglobin response with oral iron is <1.0 g/dL at day 14.[126]

Compared with oral iron, intravenous iron appears to be more effective for the treatment of IDA related to malignancy, inflammatory bowel disease, and possibly heart failure.[127][128][129][130][131][132][133][134] Supplemental intravenous iron is not beneficial in anemic critically ill trauma patients.[135]

Intravenous iron should be considered as a first-line treatment for selected patients with inflammatory bowel disease, including those with active disease or previous intolerance of oral iron.[119] Weekly low-dose iron in hemodialysis patients (even if iron-replete) may stabilize iron and hemoglobin levels, and allow for erythropoietin dose reduction.[136] One systematic review and meta-analysis found low certainty evidence that intravenous iron, compared with oral iron, increases the number of patients with chronic kidney disease who achieve target hemoglobin, and reduces the requirement for erythropoiesis stimulating agents.[137]

Intravenous iron increases the response to erythropoiesis stimulating agents in patients with cancer and chemotherapy-related anemia.[134]

Intravenous iron may be considered before or after surgery for patients with IDA who: are unable to tolerate, absorb, or adhere to oral iron; have functional iron deficiency; or have an insufficient interval between diagnosis of IDA and surgery for oral iron to be effective.[179] One randomized controlled trial found that a single dose of ferric carboxymaltose, administered to patients with anemia 10 to 42 days before elective major abdominal surgery, did not reduce the need for transfusion compared with placebo.[180] One prospective randomized trial compared treatment of postoperative IDA using ferric carboxymaltose with standard care. Patients treated with ferric carboxymaltose had significantly higher hemoglobin concentration and decreased transfusion requirements at 4 weeks.[181]

Intravenous iron may be considered in pregnancy during the second or third trimesters if benefits outweigh the risks to mother and fetus, but it should be avoided in the first trimester.[116] Guidelines advise considering the use of intravenous iron postpartum for women who have previously been intolerant of, or unresponsive to, oral iron, and/or when symptoms of anemia require prompt management.[116]

Several intravenous iron preparations are available (e.g., iron dextran, iron sucrose, sodium ferric gluconate complex, ferumoxytol, ferric carboxymaltose, and ferric derisomaltose).

Iron dextran is only available as a low-molecular-weight preparation.[143] Adverse effects include anaphylaxis, arthralgias, and myalgias.[144][145][146] In one study, use of intravenous methylprednisolone before and after total dose infusion of iron dextran decreased the risk of arthralgias and myalgias dramatically.[145] Patients who are intolerant of iron dextran can be considered for treatment with newer intravenous iron preparations. One preparation has not been found to be more efficacious than the other.[139][140][141][142] Furthermore, the risk of adverse effects may be lower with newer intravenous iron preparations compared with iron dextran.[147][148][149][150][151][152]

Iron sucrose has a similar safety profile to low-molecular-weight iron dextran.[153] Retrospective data suggest that initial administration of iron sucrose may be associated with reduced incidence of anaphylaxis compared with iron dextran (1.2 cases per 10,000 first administrations vs. 9.8 cases, respectively).[146] It appears to be safe during pregnancy, and has been shown to be more efficacious than oral iron.[118][120][154][155] In women with postpartum anemia, iron sucrose may provide a more rapid response than oral iron.[156]

Sodium ferric gluconate complex has a superior safety profile compared with iron dextran.[151] Retrospective data suggest that initial administration of ferric gluconate may be associated with reduced incidence of anaphylaxis compared with iron dextran (1.5 cases per 10,000 first administrations vs. 9.8 cases, respectively).[146]

Ferumoxytol has a more convenient dosing schedule than iron dextran and iron sucrose. It has similar efficacy and safety compared with iron sucrose and ferric carboxymaltose.[140][141][157] Retrospective data suggest that initial administration of ferumoxytol may be associated with increased incidence of anaphylaxis (4 cases per 10,000 first administrations) compared with iron sucrose (1.2 cases) or ferric carboxymaltose (0.8 cases), respectively.[146] Ferumoxytol is safe to use in patients with chronic kidney disease, but if hemodialysis is required, it should be given >1 hour after hemodialysis when blood pressure has stabilized.[158]

Ferric carboxymaltose has superior safety and efficacy compared with oral iron.[142][159] Retrospective data suggest low risk for anaphylaxis (0.8 cases per 10,000 first administrations).[146] A single dose formulation is available in some countries. It can be given as a single infusion, dependent on weight; therefore, dosing is more convenient than other preparations. It is better tolerated and more effective than other intravenous iron preparations at treating IDA in patients with inflammatory bowel disease.[160] Its use in systolic heart failure patients with iron deficiency may reduce recurrent cardiovascular hospitalizations.[161] In one randomized placebo-controlled study of patients with iron deficiency and persistently reduced left ventricular ejection fraction, treatment with ferric carboxymaltose resulted in improved cardiac function.[162]

In women with postpartum anemia, use of ferric carboxymaltose may restore hemoglobin and ferritin levels faster than other intravenous iron preparations.[163]

Ferric derisomaltose can also be given as a single infusion; therefore, dosing is more convenient than other preparations. It has superior efficacy and is faster acting than iron sucrose, but has a similar safety profile.[164][165] In one study, the likelihood of hypersensitivity reactions was 3.4 times higher with ferric derisomaltose compared with ferric carboxymaltose.[166]

Use of intravenous iron is associated with anaphylaxis, which can be life threatening.[151][167] One retrospective cohort study reported the following anaphylaxis incidence rates per 10,000 first administrations: 9.8 cases for iron dextran; 4.0 cases for ferumoxytol; 1.5 cases for ferric gluconate; 1.2 cases for iron sucrose; and 0.8 cases for ferric carboxymaltose.[146]

A test dose can be carried out, although this is not recommended in some countries as allergic reactions may still occur in patients who have not reacted to a test dose.[168] Intravenous iron should be administered in settings where appropriately trained staff and resuscitation facilities are available to manage allergic reactions.[167] Patients should be closely monitored for signs of allergy during and after every administration.[167]

Infection- and cardiovascular-related adverse events have also been reported with intravenous iron.[169][170]

Ferric carboxymaltose and ferric derisomaltose are both associated with transient hypophosphatemia; however, hypophosphatemia is significantly more common in patients treated with ferric carboxymaltose compared with patients treated with ferric derisomaltose.[171][172] Muscle fatigue and osteomalacia have been reported in patients treated with ferric carboxymaltose.[173][174][172]

Failure to respond to intravenous iron should lead to an investigation for ongoing blood loss and a questioning of the diagnosis. The diagnosis of IDA or recurrent IDA must be followed by an evaluation to determine the underlying cause.[138]

Primary options

iron dextran: children ≥4 months of age and adults: consult specialist for guidance on dose as dose depends on patient’s weight and hemoglobin values

OR

sodium ferric gluconate complex: children ≥6 years of age: 1.5 mg/kg intravenously with each hemodialysis session up to 8 total doses, maximum 125 mg/dose and 1000 mg/total course; adults: 125 mg intravenously with each hemodialysis session up to 8 total doses, maximum 1000 mg/total course

OR

iron sucrose: children ≥2 years of age and adults: consult specialist for guidance on dose as dose depends on type of dialysis

OR

ferumoxytol: adults: 510 mg intravenously as a single dose, followed by 510 mg as a single dose 3-8 days later

OR

ferric carboxymaltose: children ≥1 year of age and adults body weight <50 kg: 15 mg/kg (maximum 750 mg/dose) intravenously as a single dose initially and repeat after at least 7 days; adults body weight ≥50 kg: 750 mg intravenously as a single dose initially and repeat after at least 7 days (maximum 1500 mg/treatment course), or 15 mg/kg intravenously as a single dose (maximum 1000 mg/dose)

OR

ferric derisomaltose: adults body weight <50 kg: 20 mg/kg intravenously as a single dose; adults body weight ≥50 kg: 1000 mg intravenously as a single dose

Plus – red cell transfusion

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ACUTE
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all patients
|
with symptomatic cardiac compromise
Plus – 

red cell transfusion

Treatment recommended for ALL patients in selected patient group

Patients with symptoms of cardiovascular compromise (e.g., dyspnea at rest, chest pain, or lightheadedness) can be given red cell transfusions, but caution should be used to avoid replacing red cells too quickly to prevent volume overload.[98]

The use of a blood transfusion does not obviate the need for other forms of iron replacement, because one unit of packed red blood cells will only provide approximately 250 mg of elemental iron and would only provide enough iron to raise the hemoglobin by 1 gram.

Transfusion is not indicated in patients with cardiac compromise who are asymptomatic at rest and on exertion. Rest and treatment of anemia are advised.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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