Microcytic Anemia

Diagnostic Algorithm for Iron Deficiency Anemia

Iron Deficiency Anemia

I. Serum iron (SI), Total iron-binding capacity TIBC), and Transferrin saturation (TS)
Diagnostic:
* ↓SI and ↑TIBC
* SI/TIBC <9%
* ↓TS

II. Serum Ferritin (Ferritin)
* Ferritin <15 ng/ml (15 µg/L)
* Ferritin <45 and Likelihood ratio >= 11
  Ferritin <45 and MCV <95
* Ferritin <100 and MCV <95 and Likelihood ratio >= 0.5 and (↓SI or ↑TIBC or ↓TS or ↑Serum transferrin receptor (TfR))

Iron Deficiency Anemia + Anemia of Chronic Disease

* Ferritin < 50 ng/ml (50 µg/L) + Chronic Disease
* Ferritin <100 and MCV <95 and ↑Serum transferrin receptor (TfR)
* Ferritin <200 + Chronic renal failure and ↑Serum transferrin receptor (TfR)

Note: A serum ferritin level of < 100 ng/mL in a patient with inflammation (< 200 ng/mL in patients with chronic kidney disease) suggests that iron deficiency may be superimposed on anemia of chronic disease.

No Iron Deficiency

* MCV <95 and Ferritin >=45 and Likelihood ratio < 0.5
* MCV <95 and Ferritin >=45 and Likelihood ratio >= 0.5 ---->(↑SI or ↓TIBC or ↑TS) or ↓Serum transferrin receptor (TfR)
* MCV <95 and Ferritin >=100 and Likelihood ratio < 0.1
* MCV <95 and Ferritin >=100 and Likelihood ratio >= 0.1 ---->(↑SI or ↓TIBC or ↑TS)

Anemia of Chronic Disease

It is characterized by a microcytic or normocytic anemia and low reticulocyte count. Values for serum iron transferrin are typically low to normal, while ferritin can be normal or elevated.

Iron Deficiency Anemia

The prevalence of iron deficiency anemia is 2 percent in adult men, 9 to 12 percent in non-Hispanic white women, and nearly 20 percent in black and Mexican-American women. Nine percent of patients older than 65 years with iron deficiency anemia have a gastrointestinal cancer when evaluated. The U.S. Preventive Services Task Force currently recommends screening for iron deficiency anemia in pregnant women but not in other groups. Routine iron supplementation is recommended for high-risk infants six to 12 months of age. Iron deficiency anemia is classically described as a microcytic anemia. The differential diagnosis includes thalassemia, sideroblastic anemias, some types of anemia of chronic disease, and lead poisoning.

Iron Deficiency Anemia

Of about 15 mg/day of dietary iron, adults absorb only 1 mg, which is the approximate amount lost daily by cell desquamation from the skin and intestines. In iron depletion, absorption increases due to the suppression of hepcidin, a key regulator of iron metabolism; however, absorption rarely increases to > 6 mg/day unless supplemental iron is added. Children have a greater need for iron and appear to absorb more to meet this need.

Stages of iron deficiency

Laboratory test results help stage iron deficiency anemia.

Stage 1 is characterized by decreased bone marrow iron stores; hemoglobin (Hb) and serum iron remain normal, but the serum ferritin level falls to < 20 ng/mL. The compensatory increase in iron absorption causes an increase in iron-binding capacity (transferrin level).

During stage 2, erythropoiesis is impaired. Although the transferrin level is increased, the serum iron level decreases; transferrin saturation decreases. Erythropoiesis is impaired when serum iron falls to < 50 μg/dL (< 9 μmol/L) and transferrin saturation to < 16%. The serum transferrin receptor level rises (> 8.5 mg/L).

During stage 3, anemia with normal-appearing RBCs and indices develops.

During stage 4, microcytosis and then hypochromia develop.

During stage 5, iron deficiency affects tissues, resulting in symptoms and signs.

Diagnosis of iron deficiency anemia prompts consideration of its cause, usually bleeding. Patients with obvious blood loss (eg, women with menorrhagia) may require no further testing. Men and postmenopausal women without obvious blood loss should undergo evaluation of the GI tract, because anemia may be the only indication of an occult GI cancer. Rarely, chronic epistaxis or GU bleeding is underestimated by the patient and requires evaluation in patients with normal GI study results.

Differential Diagnosis of Microcytic Anemia

• Iron Deficiency
M>H, ↑RDW, ↓Serum iron, ↑TIBC, Transferrin Saturation<10%, Ferritin<12
• Iron-Transport Deficiency
M>H, ↑RDW, ↓Serum iron, ↓TIBC, Transferrin Saturation 0%, Ferritin Usually normal
• Sideroblastic Iron Utilization
M>H, May be normocytic, ↑RDW, ↑Serum iron, Normal TIBC, Transferrin Saturation >50%, Ferritin>400
Polychromatophilic targeted cells, Stippled RBCs, Bone marrow ringed sideroblasts
• Chronic disease/inflammation
Frequently normocytic, Normal RDW, Normal or ↓Serum iron, Normal or ↓TIBC, Transferrin Saturation Normal or decreased (0–50%), Ferritin 30-400

ACCRUFER (ferric maltol)

1.INDICATIONS AND USAGE
ACCRUFER is indicated for the treatment of iron deficiency in adults.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dosage of ACCRUFER is 30 mg twice daily, taken 1 hour before or 2 hours after a meal. Do not open, break, or chew ACCRUFER capsules.
Treatment duration will depend on the severity of iron deficiency but generally at least 12 weeks of treatment is required. The treatment should be continued as long as necessary until ferritin levels are within the normal range.
3 DOSAGE FORMS AND STRENGTHS
Capsules: ACCRUFER contains 30 mg iron, as ferric maltol, in red capsules printed with “30”.
Dosing Recommendations
Inform patients to take ACCRUFER as directed on an empty stomach, at least 1 hour before or 2 hours after meals. Instruct patients on concomitant medications that should be dosed apart from ACCRUFER.

Note:
Broad label approval Accrufer in USA
Accrufer’s confirmed efficacy, together with its good tolerability and mode of absorption - by which the body absorbs only as much iron from Accrufer as it needs - means that the product could be the ideal choice for iron deficient patients who cannot tolerate salt-based oral iron alternatives. These features, combined with the noninferiority results from the AEGIS-H2H study announced in March 2019, mean that treatment with Accrufer might remove the need for patients to progress to intravenous iron therapy, leading to a change in the current paradigm for the treatment of iron deficiency anaemia.

** ferric carboxymaltose (Injectafer)
Parenteral iron replacement product
For iron deficiency anemia in adults who have intolerance to or an unsatisfactory response to oral iron; also for non-dialysis dependent chronic kidney disease
Anaphylactic-type reactions, including life-threatening and fatal, have been reported with use of ferric carboxymaltose
■ For the treatment of iron-deficiency anemia in patients who are intolerant to or have had an unsatisfactory response to oral iron, or those who have non-dialysis dependent chronic kidney disease.
NOTE: The dosage of ferric carboxymaltose is expressed in mg of elemental iron. Each mL contains 50 mg of elemental iron.
Intravenous dosage
Adults weighing 50 kg or more
750 mg/dose IV for 2 doses separated by at least 7 days. Do not exceed 1500 mg of iron per course. Treatment may be repeated if iron deficiency anemia reoccurs. Heart failure guidelines suggest intravenous iron replacement may be reasonable in patients with NYHA class II and III heart failure and iron deficiency to improve functional status and quality of life.
Adults weighing less than 50 kg
15 mg/kg/dose IV for 2 doses separated by at least 7 days. Treatment may be repeated if iron deficiency anemia reoccurs. Heart failure guidelines suggest intravenous iron replacement may be reasonable in patients with NYHA class II and III heart failure and iron deficiency to improve functional status and quality of life.

** ferumoxytol (Feraheme)
Intravenous iron replacement product
Associated with fatal and serious hypersensitivity reactions
■ For the treatment of iron-deficiency anemia in patients with chronic kidney disease or intolerance or unsatisfactory response to oral iron.
510 mg IV followed by a second 510 mg IV dose 3 to 8 days later.
The recommended dose may be readministered to patients with persistent or recurrent iron deficiency anemia.
Cumulative doses of up to 2.04 g were administered to some patients with chronic kidney disease in premarketing clinical trials.
■ For use as a magnetic resonance imaging (MRI)† contrast agent.

Note:
Treatment of iron-deficiency anemia in patients with chronic kidney disease
The incidence of severe hypophosphatemia (0.4%) was less with FERAHEME than with Injectafer (38.7%)

WARNING: RISK FOR SERIOUS HYPERSENSITIVITY/ANAPHYLAXIS REACTIONS
Fatal and serious hypersensitivity reactions including anaphylaxis have occurred in patients receiving Feraheme. Initial symptoms may include hypotension, syncope, unresponsiveness, cardiac/cardiorespiratory arrest.
Only administer Feraheme as an intravenous infusion over at least 15 minutes and only when personnel and therapies are immediately available for the treatment of anaphylaxis and other hypersensitivity reactions.
Observe for signs or symptoms of hypersensitivity reactions during and for at least 30 minutes following Feraheme infusion including monitoring of blood pressure and pulse during and after Feraheme administration.
Hypersensitivity reactions have occurred in patients in whom a previous Feraheme dose was tolerated.

Adverse Reactions
The most common adverse reactions (≥ 2%) are diarrhea, headache, nausea, dizziness, hypotension, constipation, and peripheral edema.

Hypersensitivity reactions to intravenous iron: guidance for risk minimization and management

Algorithm outlining grading and management of acute hypersensitivity reactions to intravenous iron infusions.

Etiology

Anemia of chronic disease occurs as part of a chronic inflammatory disorder, most often chronic infection, autoimmune disease (especially RA), kidney disease, or cancer; however, the same process appears to begin acutely during virtually any infection or inflammation, including trauma or post-surgery. (See also Anemia of Renal Disease.)

Three pathophysiologic mechanisms have been identified:
• Slightly shortened RBC survival, thought to be due to release of inflammatory cytokines, occurs in patients with cancer or chronic granulomatous infections.
• Erythropoiesis is impaired because of decreases in both erythropoietin (EPO) production and marrow responsiveness to EPO.
• Iron metabolism is altered due to an increase in hepcidin, which inhibits iron absorption and recycling, leading to iron sequestration.

Reticuloendothelial cells retain iron from senescent RBCs, making iron unavailable for hemoglobin (Hb) synthesis. There is thus a failure to compensate for the anemia with increased RBC production. Macrophage-derived cytokines (eg, IL-1-beta, tumor necrosis factor-alpha, interferon-beta) in patients with infections, inflammatory states, and cancer contribute to the decrease in EPO production and the impaired iron metabolism by increasing hepatic synthesis of hepcidin.

Diagnosis

• Symptoms and signs of underlying disorder
• CBC and serum iron, ferritin, transferrin, and reticulocyte count

Clinical findings in anemia of chronic disease are usually those of the underlying disorder (infection, inflammation, or cancer). Anemia of chronic disease should be suspected in patients with microcytic or normocytic anemia who also have chronic illness, infection, inflammation, or cancer. If anemia of chronic disease is suspected, serum iron, transferrin, reticulocyte count and serum ferritin are measured. Hb usually is > 8 g/dL unless an additional mechanism contributes to anemia, such as concomitant iron deficiency (see table Differential Diagnosis of Microcytic Anemia Due to Decreased RBC Production).

A serum ferritin level of < 100 ng/mL in a patient with inflammation (< 200 ng/mL in patients with chronic kidney disease) suggests that iron deficiency may be superimposed on anemia of chronic disease. However, serum ferritin may be falsely elevated as an acute-phase reactant.

Treatment

• Treatment of underlying disorder
• Sometimes recombinant erythropoietin (EPO) and iron supplements

Treatment of anemia of chronic disease requires treating the underlying disorder. Because the anemia is generally mild, transfusions usually are not required.

Recombinant EPO has been shown to be most useful in the setting of chronic kidney disease. Because both reduced production of and marrow resistance to EPO occur, the EPO dose may need to be 150 to 300 units/kg sc 3 times/wk. A good response is likely if, after 2 wk of therapy, Hb has increased > 0.5 g/dL and serum ferritin is < 400 ng/mL.

Iron supplements are required to ensure an adequate response to EPO. However, careful monitoring of Hb response is needed because adverse effects (eg, venous thromboembolism, myocardial infarction, death) may occur when Hb rises to > 12 g/dL.

Key Points

• Almost any chronic infection, inflammation, or cancer can cause anemia; hemoglobin usually is > 8 g/dL unless an additional mechanism contributes.
• Multiple factors are involved, including shortened RBC survival, impaired erythropoiesis, and impaired iron metabolism.
• Anemia is initially normocytic and then can become microcytic.
• Serum iron and transferrin are typically decreased, while ferritin is normal to increased.
• Treat the underlying disorder and consider recombinant EPO.

Anemia of Renal Disease

Anemia of renal disease is a hypoproliferative anemia resulting primarily from deficient erythropoietin (EPO) or a diminished response to it; it tends to be normocytic and normochromic. Treatment includes measures to correct the underlying disorder and supplementation with EPO and sometimes iron.

Anemia in chronic renal disease is multifactorial. The most common mechanism is
• Hypoproliferation due to decreased EPO production

Other factors include
• Uremia (in which mild hemolysis is common due to an increase in RBC deformity)
• Blood loss due to dysfunctional platelets, dialysis, and/or angiodysplasia
• Secondary hyperparathyroidism

Less common is RBC fragmentation (traumatic hemolytic anemia), which occurs when the renovascular endothelium is injured (eg, in malignant hypertension, membranoproliferative glomerulonephritis, polyarteritis nodosa, or acute cortical necrosis).

The deficiency in renal production of EPO and the severity of anemia do not always correlate with the extent of renal dysfunction; anemia occurs when creatinine clearance is < 45 mL/min. Renal glomerular lesions (eg, due to amyloidosis, diabetic nephropathy) generally result in the most severe anemia for their degree of excretory failure.

Diagnosis

• CBC and peripheral smear

Diagnosis of anemia of renal disease is based on demonstration of renal insufficiency, normocytic anemia, and peripheral reticulocytopenia.

Bone marrow may show erythroid hypoplasia. RBC fragmentation on the peripheral smear, particularly if there is thrombocytopenia, suggests simultaneous traumatic hemolysis.

Treatment

• Treatment of underlying renal disease
• Sometimes, erythropoietin plus iron supplements

Treatment of anemia of renal disease is directed at
• Improving renal function
• Increasing RBC production

If renal function returns to normal, anemia is slowly corrected.

In patients receiving long-term dialysis, EPO, beginning with 50 to 100 units/kg IV or sc 3 times/wk with iron supplements, is the treatment of choice. In almost all cases, maximum increases in RBCs are reached by 8 to 12 wk. Reduced doses of EPO (about one half the induction dose) can then be given 1 to 3 times/wk. Transfusions are rarely necessary. Careful monitoring of the response is needed to avoid adverse effects when hemoglobin increases to > 12 g/dL.

Three pathophysiologic mechanisms have been identified:
• Slightly shortened RBC survival, thought to be due to release of inflammatory cytokines, occurs in patients with cancer or chronic granulomatous infections. • Erythropoiesis is impaired because of decreases in both erythropoietin (EPO) production and marrow responsiveness to EPO.
• Iron metabolism is altered due to an increase in hepcidin, which inhibits iron absorption and recycling, leading to iron sequestration.

Reticuloendothelial cells retain iron from senescent RBCs, making iron unavailable for hemoglobin (Hb) synthesis. There is thus a failure to compensate for the anemia with increased RBC production. Macrophage-derived cytokines (eg, IL-1-beta, tumor necrosis factor-alpha, interferon-beta) in patients with infections, inflammatory states, and cancer contribute to the decrease in EPO production and the impaired iron metabolism by increasing hepatic synthesis of hepcidin.

A serum ferritin level of < 100 ng/mL in a patient with inflammation (< 200 ng/mL in patients with chronic kidney disease) suggests that iron deficiency may be superimposed on anemia of chronic disease. However, serum ferritin may be falsely elevated as an acute-phase reactant.

Treatment
• Treatment of underlying disorder
• Sometimes recombinant erythropoietin (EPO) and iron supplements

Treatment of anemia of chronic disease requires treating the underlying disorder. Because the anemia is generally mild, transfusions usually are not required.

Recombinant EPO has been shown to be most useful in the setting of chronic kidney disease. Because both reduced production of and marrow resistance to EPO occur, the EPO dose may need to be 150 to 300 units/kg sc 3 times/wk. A good response is likely if, after 2 wk of therapy, Hb has increased > 0.5 g/dL and serum ferritin is < 400 ng/mL.

Iron supplements are required to ensure an adequate response to EPO. However, careful monitoring of Hb response is needed because adverse effects (eg, venous thromboembolism, myocardial infarction, death) may occur when Hb rises to > 12 g/dL.

Anemia of Renal Disease

Anemia of renal disease is a hypoproliferative anemia resulting primarily from deficient erythropoietin (EPO) or a diminished response to it; it tends to be normocytic and normochromic. Treatment includes measures to correct the underlying disorder and supplementation with EPO and sometimes iron.

Anemia in chronic renal disease is multifactorial. The most common mechanism is
• Hypoproliferation due to decreased EPO production

Other factors include
• Uremia (in which mild hemolysis is common due to an increase in RBC deformity)
• Blood loss due to dysfunctional platelets, dialysis, and/or angiodysplasia
• Secondary hyperparathyroidism

Less common is RBC fragmentation (traumatic hemolytic anemia), which occurs when the renovascular endothelium is injured (eg, in malignant hypertension, membranoproliferative glomerulonephritis, polyarteritis nodosa, or acute cortical necrosis).

The deficiency in renal production of EPO and the severity of anemia do not always correlate with the extent of renal dysfunction; anemia occurs when creatinine clearance is < 45 mL/min. Renal glomerular lesions (eg, due to amyloidosis, diabetic nephropathy) generally result in the most severe anemia for their degree of excretory failure.

Diagnosis

• CBC and peripheral smear

Diagnosis of anemia of renal disease is based on demonstration of renal insufficiency, normocytic anemia, and peripheral reticulocytopenia.

Bone marrow may show erythroid hypoplasia. RBC fragmentation on the peripheral smear, particularly if there is thrombocytopenia, suggests simultaneous traumatic hemolysis.

Treatment

• Treatment of underlying renal disease
• Sometimes, erythropoietin plus iron supplements

Treatment of anemia of renal disease is directed at
• Improving renal function
• Increasing RBC production

If renal function returns to normal, anemia is slowly corrected.

In patients receiving long-term dialysis, EPO, beginning with 50 to 100 units/kg IV or sc 3 times/wk with iron supplements, is the treatment of choice. In almost all cases, maximum increases in RBCs are reached by 8 to 12 wk. Reduced doses of EPO (about one half the induction dose) can then be given 1 to 3 times/wk. Transfusions are rarely necessary. Careful monitoring of the response is needed to avoid adverse effects when hemoglobin increases to > 12 g/dL.

Anemia of chronic kidney disease: Treat it, but not too aggressively

Anemia of renal disease is common and is associated with significant morbidity and death. It is mainly caused by a decrease in erythropoietin production in the kidneys and can be partially corrected with erythropoiesis-stimulating agents (ESAs). However, randomized controlled trials have shown that using ESAs to target normal hemoglobin levels can be harmful, and have called into question any benefits of ESA treatment other than avoidance of transfusions.

KEY POINTS
• Before treating with ESAs, it is necessary to investigate and rule out underlying treatable conditions such as iron or vitamin deficiencies.
• Recognizing anemia in chronic kidney disease is important and often involves participation by the primary care physician, especially in early disease when chronic kidney disease may be mild.
• The only proven benefit of ESA therapy is avoidance of blood transfusions.
• ESAs should not be used to increase the hemoglobin concentration above 13 g/dL. In end-stage renal disease, the goal of therapy is to maintain levels at a target no higher than 11.5 g/dL. In nondialysis-dependent chronic kidney disease, the decision to prescribe ESA therapy should be individualized.

Anemia is a frequent complication of chronic kidney disease, occurring in over 90% of patients receiving renal replacement therapy. It is associated with significant morbidity and mortality. While its pathogenesis is typically multifactorial, the predominant cause is failure of the kidneys to produce enough endogenous erythropoietin. The clinical approval of recombinant human erythropoietin in 1989 dramatically changed the treatment of anemia of chronic kidney disease, but randomized controlled trials yielded disappointing results when erythropoiesis-stimulating agents (ESAs) were used to raise hemoglobin to normal levels.

This article reviews the epidemiology and pathophysiology of anemia of chronic kidney disease and discusses the complicated and conflicting evidence regarding its treatment

Mechanism of anemia in CKD

Kidney production of erythropoietin (EPO) is decreased --> EPO levels are insufficient
Red blood cell production and Hemoglobin production Decrease
Transferrin saturation declines
Hepcidin production by the liver prevents release of iron into plasma

Anemia affects nearly all patients with HDD-CKD and is caused by several factors:
• Insufficient production of renal EPO, which leads to decreased red blood cell production
• Decreased iron availability due to inflammation and increased hepcidin levels, which inhibits iron absorption and release of stored iron
• Regular blood loss due to uremia and hemodialysis, which results in the loss of ~5 to 7 mg of iron per treatment

Macromolecular IV Iron Mechanism of Action

• Chronic inflammation in HDD-CKD patients increases hepcidin production
• Hepcidin increases iron stores by preventing release of iron into plasma
• Macromolecular iron is administered in hemodialysis patients to replace dialysis-related iron loss and overcome iron deficiency anemia
• Macromolecular iron is taken up and processed by the macrophages of the reticuloendothelial system (RES), but becomes sequestered within the RES
• Transferrin saturation declines due to iron sequestration
• Macromolecular iron exacerbates functional iron deficiency
Iron bioavailability
Iron stores and iron overload
Toxicity
Inflammation
Hepcidin production
Macromolecular iron is not the optimal approach to iron maintenance. It may contribute to functional iron deficiency, which resembles traditional iron deficiency
Macromolecular iron has a carbohydrate shell which must be removed by the RES (macrophages) before the iron is available for use. Chronic inflammation due to CKD causes increased levels of hepcidin, which prevents the release of macromolecular iron from the RES. This often results in a considerable proportion of macromolecular iron becoming trapped in the body (primarily the liver). Macromolecular iron has a carbohydrate shell and cannot be used by the body until it is processed by reticuloendothelial cells (macrophages).
Macromolecular iron often:
Provides limited bioavailable iron
Increases ferritin levels and risk of iron overload
Increases exposure to nontransferrin-bound iron (NTBI) and risk of oxidative stress
Increases risk of inflammation and may increase risk of infection
Further increases hepcidin production

TRIFERIC (Ferric Pyrophosphate Citrate Solution)

TRIFERIC Mechanism of Action
• TRIFERIC crosses the dialyzer membrane via dialysate
• Small molecule TRIFERIC avoids iron sequestration
• TRIFERIC donates iron directly and completely to transferrin
• Transferrin-bound iron is immediately delivered to the bone marrow for hemoglobin formation
• TRIFERIC restores the approximate amount of iron lost during hemodialysis procedure
TRIFERIC efficiently replaces the ~5 to 7 mg of iron lost throughout the course of a hemodialysis session in real time.
TRIFERIC is administered through the dialysate and is similar to naturally absorbed iron in that it donates iron directly and completely to transferrin in the bloodstream and is immediately available for hemoglobin production.
Benefits of the TRIFERIC molecular design:
• Efficiently provides bioavailable iron to replace what is lost during hemodialysis
• Bypasses hepcidin blockade of iron and does not increase ferritin levels or risk of iron overload
• Donates iron directly and completely to transferrin to become available for hemoglobin production

INDICATION
TRIFERIC is indicated for the replacement of iron to maintain hemoglobin in adult patients with hemo-dialysis-dependent chronic kidney disease (HDD-CKD).
Limitations of Use
• TRIFERIC is not intended for use in patients receiving peritoneal dialysis.
• TRIFERIC has not been studied in patients receiving home hemodialysis.

TRIFERIC is the first and only FDA-approved treatment indicated for the replacement of iron to maintain hemoglobin in adult patients with hemodialysis-dependent chronic kidney disease (HDD-CKD).
TRIFERIC is administered through the dialysate and replaces the iron lost during hemodialysis in real-time to maintain hemoglobin

AURYXIA (ferric citrate)

Tablets: 210 mg ferric iron, equivalent to 1 g ferric citrate
■ Hyperphosphatemia in Chronic Kidney Disease on Dialysis: • Starting dose is 2 tablets orally 3 times per day with meals
• Adjust dose by 1 to 2 tablets as needed to maintain serum phosphorus at target levels, up to a maximum of 12 tablets daily.
Dose can be titrated at 1-week or longer intervals.
■ Iron Deficiency Anemia in Chronic Kidney Disease Not on Dialysis:
• Starting dose is 1 tablet orally 3 times per day with meals
• Adjust dose as needed to achieve and maintain hemoglobin goal,
up to a maximum of 12 tablets daily