The goal of anemia therapy is to increase the hemoglobin level, which will improve the red cell oxygen-carrying capacity, alleviate symptoms, and prevent anemia complications. The underlying cause of anemia must be determined to guide therapy.
Nonpharmacologic therapy plays a limited role in the management of anemia. Diets lacking key nutrients are rarely the sole cause of anemia in the United States. Therefore, ingesting a diet rich in iron, folic acid, or vitamin B12 should not be the only modality of treatment. Symptomatic anemia patients with a hemoglobin concentration less than 7 g/dL (70 g/L or 4.34 mmol/L) are candidates for transfusion of red blood cells.12,13 Because of the risk of infection, immunosuppression, and microcirculatory complications, the threshold for transfusion has been debated. Generally, only patients requiring immediate correction receive blood transfusions.
Treatment of iron-deficiency anemia is oral iron therapy with 200 mg of elemental iron daily. There are different iron products and salt forms available (Table 10-4), with different amounts of elemental iron in each product. Iron supplementation resolves anemia by replacing iron stores in the body that are necessary for red blood cell production and maturation.12-15 A response (presence of reticulocytosis) should be seen in 7 to 10 days and the hemoglobin values should rise by approximately 1 g/dL (10 g/L or 0.62 mmol/L) per week. Patients should be reassessed if hemoglobin values do not increase by 2 g/dL (20 g/L or 1.24 mmol/L) in 3 weeks. Hemoglobin levels should normalize in 6 to 8 weeks, but iron therapy may continue for 6 to 12 months in order to fully replenish iron stores. Iron dosing should be divided into two to three daily doses, depending upon the oral formulation utilized. Maximal absorption is achieved on an empty stomach (1 hour before or 2 hours after a meal); however, patients who cannot tolerate iron on an empty stomach may take it with food. Side effects for oral iron include: dark/discolored stools, abdominal pain, nausea, constipation, and heartburn. Iron may bind to medications causing a decreased absorption of the interacting drug; examples include fluoroquinolones, tetracyclines, and phenytoin. This interaction is avoided if the administration of iron and the interacting drug are separated by 2 to 4 hours.
TABLE 10-4 Iron Products (Oral and Intravenous) and Elemental Iron Content ||Download (.pdf)
TABLE 10-4 Iron Products (Oral and Intravenous) and Elemental Iron Content
|Salt Form||Brand Name||Elemental Iron Content per Dose Form|
|Ferrous sulfate||Feosol||65 mg/325 mg tablet 60 mg/300 mg tablet|
|Ferrous sulfate, anhydrous||N/A||65 mg/200 mg tablet|
39 mg/325 mg tablet
37 mg/300 mg tablet
|Ferrous fumarate||Feostat||33 mg/100 mg capsule|
|Polysaccharide-iron complex||Niferex||150 mg/capsule 50 mg/tablet|
|Iron sucrose||Venofer||20 mg/mL|
|Sodium ferric gluconate||Ferrlecit||62.5 mg/5 mL|
Parenteral iron therapy is for patients unable to tolerate the oral formulation, noncompliance, or nonresponders (malabsorption).16,17Table 10-4 lists the three parenteral formulations of iron. Iron dextran is FDA approved for the treatment of iron deficiency in patients unable to tolerate the oral formulation. Sodium ferric gluconate and iron sucrose are indicated to treat anemia associated with CKD in patient receiving erythropoietin products. Side effects associated with parenteral products are: anaphylaxis (dextran only), arthralgias, arrhythmias, hypotension, flushing, and pruritus.17-18 A test dose of iron dextran should be given on the first day of therapy and patients should be observed for 1 hour for the hypersensitivity reaction. The remaining iron dextran dose (dose minus test dose) should be given if patients tolerate the test dose.
Vitamin B12 and Folic Acid Anemia
Vitamin B12 and folic acid anemias are treated by replacing the missing nutrient. Both vitamin B12 and folic acid are essential for erythrocyte production and maturation. Replacing these factors allows for normal DNA synthesis and erythropoiesis.
The goals of treatment for vitamin B12 deficiency include reversal of hematologic manifestations, replacement of body stores, and prevention or resolution of neurologic manifestations. Early treatment is paramount because neurologic damage may be irreversible if the deficiency is not detected and corrected within months. Permanent disabilities range from mild paresthesias and numbness to memory loss and psychosis.
Vitamin B12 (cyanacobalamin) administered orally or parenterally is effective in treating vitamin B12 anemia.19-20 Parenteral use is more common because absorption is higher and more predictable. Subcutaneous or intramuscular administration may be given. A common oral dosing regimen is 1000 to 2000 μg/d. Parenteral regimens consist of daily injections of 1000 μg for 1 week to saturate vitamin B12 stores in the body and resolve clinical manifestations. Parenteral administration can be given weekly for 1 month and monthly thereafter for maintenance. Vitamin B12 nasal spray is available for patients in remission following IV vitamin B12, who have no nervous system involvement. The response to therapy is quick, neurologic symptoms and megaloblastic cells disappear within days and hemoglobin levels increase after a week of therapy. Vitamin B12 is well tolerated and has minimal adverse effects. Injection site pain, pruritus, fluid retention, rash, and diarrhea have been reported. Drug interactions with omeprazole and ascorbic acid may decrease oral absorption.21
Folic acid deficiency is a common cause of vitamin anemia, largely resulting with pregnancy and excessive alcohol intake. An initial daily dose of oral folic acid 1 mg/d is effective. Resolution of symptoms is prompt, occurring within days of starting therapy. Hemoglobin levels will start to rise after 2 weeks and may take 2 to 4 weeks to resolve the anemia completely. If the underlying deficiency is corrected, folic acid replacement can be discontinued. Folic acid is well tolerated. Nonspecific adverse effects are: allergic reactions, flushing, malaise, and rash.22-23
Anemia of Chronic Disease
Anemia of chronic disease (ACD) is a term describing anemia caused by underlying chronic conditions. These chronic conditions include cancer, chronic kidney disease, and other inflammatory disorders. Treatment of ACD is less specific than treatment of other anemias. In patients with anemia from cancer or chronic kidney disease, therapy with epoetin or darbepoetin can increase hemoglobin, decrease transfusions, and improve quality of life.
Chemotherapy Induced Anemia
The National Comprehensive Cancer Network (NCCN) recommends an anemia work-up for patients with hemoglobin levels less than 11 g/dL (110 g/L or 6.8 mmol/L). Cancer patients with chemotherapy-related anemia who are symptomatic or asymptomatic with risk factors (extensive transfusion history or myelosuppressive therapy) qualify for treatment with erythropoietic agents such as epoetin-alfa or darbepoetin. Epoetin is recombinant human erythropoietin and darbepoetin is structurally similar to endogenous erythropoietin. Both bind to the same receptor to simulate red blood cell production. Darbepoetin differs from epoetin in that it has a longer half-life due to additional N-linked carbohydrate side chains. The response to erythropoietin products must be monitored closely to prevent adverse effects. Adverse events include hypertension, thrombosis, and tumor progression. Concomitant drugs with the same adverse-event profile may increase a patient's risk for side effects. Patient survival may be decreased if the hemoglobin level is titrated above 11 to 12 g/dL (110-120 g/L or 6.82-7.44 mmol/L). Hemoglobin values should be monitored at least every 2 weeks. The following are recommendations for modification of the erythropoietin agent:
- If hemoglobin levels rise above 1 g/dL (10g/L or 0.62 mmol/L) or greater in 2 weeks, decrease the dose by 25%.
- If hemoglobin levels rise above 12 g/dL (120 g/L or 7.44 mmol/L), hold dose until hemoglobin levels fall below 12 g/dL. Therapy can be restarted after hemoglobin levels fall, but decrease the dose by 25%.
- Increase dose by 50% in nonresponding patients. Nonresponding is defined as patients who do not exhibit at least a 1 g/dL (10 g/L or 0.62 mmol/L) increase in hemoglobin after 4 to 6 weeks. In addition, if their hemoglobin has not increased by 1 g/dL after 8 weeks of therapy, the drug should be discontinued.
Table 10-5 provides dosing recommendations for chemotherapy-related anemia.
TABLE 10-5 Erythropoietin Products and Doses for Anemia for Chemotherapy and CKD ||Download (.pdf)
TABLE 10-5 Erythropoietin Products and Doses for Anemia for Chemotherapy and CKD
|Epoetin-Alfa (Epogen, Procrit)||Darbepoetin-Alfa (Aranesp)|
|Cancer/chemotherapy dosing regimens||150 units/kg subcutaneously three times per week 40,000 units subcutaneously once every week||2.25 μg/kg subcutaneously once every week 3 μg/kg subcutaneously once every 2 weeks; may increase to 5 μg/kg 200 μg subcutaneous fixed dose every 2 weeks, may increase to 300 μg 300-500 μg every 3 weeks|
|CKD dosing regimensa||50-100 units/kg subcutaneously three times per week||0.45 μg/kg subcutaneously once every week 0.75 μg/kg subcutaneously once every 2 weeks|
Cancer patients may have concurrent iron deficiency anemia secondary to cancer. It is imperative that these patients have iron studies performed to assess adequate iron stores needed to drive hematopoiesis.8,24-27
Patients with chronic kidney disease progress through five stages of disease based upon glomerular filtration rate (GFR). Anemia is a common development in patients with CKD, and evaluation and treatment should be initiated in patients with stage 3 CKD (GFR less than 60). CKD anemia typically is a normocytic, normochromic anemia that is due to erythropoietin deficiency. Therefore, therapy with epoetin or darbepoetin is effective in treating CKD anemia. The target hemoglobin for CKD patients is similar to the target for chemotherapy anemia, but requires lower doses (see Table 10-5). Epoetin doses should be:
- Decreased by 25% if Hgb increases by greater than 1 g/dL in 2 weeks
- Increased by 25% if Hgb increases by less than 1 g/dL in 4 weeks
It can take up to 6 to 12 weeks to see the maximal effects, so doses should not be changed more frequently than once every 4 weeks.
Iron stores in patients with CKD should be maintained. If iron stores are not maintained, epoetin and darbepoetin will not be effective. Oral iron therapy can be used, but is often ineffective, particularly in dialysis patients.8,27-28 Therefore, IV iron therapy (see Table 10-4) is used extensively in these patients.