EPOGEN

General Administration Information
For storage information, see the specific product information within the How Supplied section.

Route-Specific Administration

Injectable Administration
-Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Epoetin alfa should be clear and colorless.
-Protect vials from light.
-Do not shake or freeze.
-Do not reenter preservative-free vials. Multidose vials with preservatives are available.
-Do not dilute. Do not administer with other drug solutions in general; however, preservative-free epoetin alfa may be admixed in a syringe with bacteriostatic 0.9% Sodium Chloride Injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) in a 1:1 ratio using aseptic technique at the time of administration. Do not use bacteriostatic saline when administering to neonates, infants, and pregnant or lactating women.
-Storage: Discard unused epoetin alfa in preservative-free vials. Multidose vials can be kept refrigerated at 2 to 8 degrees C (36 to 46 degrees F) for 21 days once opened.
Intravenous Administration
Intermittent IV Infusion
-May be injected directly into a vein or via the venous return line of the dialysis tubing at the end of a dialysis session.

Subcutaneous Administration
-Inject subcutaneously taking care not to inject intradermally.

The manufacturer states that in pediatric patients with chronic renal failure, the pattern of adverse reactions is similar to that found in adults. In pediatric cancer patients on chemotherapy, although not directly compared, the safety data from studies is similar to that obtained from the epoetin alfa studies in adult patients. In studies of premature neonates, the administration of epoetin alfa is usually well tolerated and this patient population does not experience the same complications that have been observed in adults.

In preliminary studies of epoetin alfa in pediatric patients, neutropenia, depletion of iron stores, and a possible association with sudden infant death syndrome (SIDS) were reported. In a small study that included 7 patients (gestational age 30 to 33 weeks, postnatal age 21 to 33 days) receiving epoetin alfa for anemia of prematurity, a transient increase in platelet count (6 of 7 neonates) was reported. The mean baseline count of 387 +/- 103 x 109/L increased to 504 +/- 99 x 109/L and 561 +/- 95 x 109/L on days 3 and 7, respectively; by day 14 it had returned to its baseline value. The mean ANC decreased from 2.2 +/- 2.6 x 109/L on day 0 to 0.8 +/- 0.4 x 109/L on day 56 (p = 0.2). In a study evaluating 157 premature neonates receiving epoetin alfa to decrease the need for blood transfusions, there were no differences between neonates in the epoetin alfa and placebo groups with respect to platelet counts, white blood cell counts, or neutrophil counts. In the same study, there were no differences in the rates of infections or necrotizing enterocolitis in the 2 groups. Studies have also suggested that mortality is not increased in premature neonates receiving epoetin alfa.

Patients receiving epoetin alfa have developed hypertension, often within the first several months of therapy. Most commonly, hypertension occurs in adult patients with chronic renal failure receiving dialysis (27.7%), but it has also been reported in other patient populations including chronic renal failure patients not receiving dialysis (13.7%) and surgical patients (3% to 6%). Of note, after initiation and titration of epoetin alfa, approximately 25% of adult patients on dialysis required initiation of or increases in antihypertensive therapy. In a study of 152 premature neonates, 2 neonates receiving epoetin alfa developed systemic hypertension; 1 during week 2 and the other during week 6 of treatment. Hypertension has been associated with the acute increase in hematocrit during therapy, but other factors are involved. A significant increase in blood pressure has been inversely related to the pretreatment hematocrit concentration, but not the epoetin alfa dose or baseline blood pressure. Studies have suggested that hypertension may result from a reversal in anemic hypoxic peripheral vasodilation that occurs with improving cardiac output. Increases in blood viscosity have been suggested to play a role, but no significant difference in blood viscosity has been noted in hypertensive vs. normotensive patients. Patients with preexisting hypertension may require an increase in antihypertensive therapy. Take special care to closely monitor and aggressively control blood pressure. Advise patients regarding the importance of compliance with antihypertensive therapy and dietary restrictions. If blood pressure is difficult to control by initiation of appropriate measures, hemoglobin may be reduced by decreasing or withholding the dose of epoetin alfa. A clinically significant decrease in hemoglobin may not be observed for several weeks.

Hypertensive encephalopathy and seizures have been observed in adult patients with chronic renal failure treated with epoetin alfa. A sudden rise in blood pressure, associated with increased hematocrit, is believed to be the mechanism for seizures. Monitor hemoglobin weekly after treatment initiation and after each dosage adjustment, until the hemoglobin concentration is stable. Reduce the dose of epoetin alfa if the increase in hemoglobin exceeds 1 g/dL in any 2-week period, because of the possible association of excessive rate of rise of hemoglobin with an exacerbation of hypertension. Headache was reported during clinical trials for adult cancer patients (5% vs. 4% placebo) and in adult surgery patients (10% to 18% vs. 9% placebo). Dizziness was reported during trials of adult patients with chronic renal failure on dialysis (9.5% vs. 8.3% placebo). In trials conducted in patients with cancer, insomnia (6% vs. 2% placebo) and depression (5% vs. 4%) were reported.

As with all therapeutic proteins, there is a potential for immunogenicity. The presence of neutralizing antibodies (i.e., anti-erythropoietin antibodies) has been associated with the development of pure red cell aplasia (PRCA) in patients receiving recombinant erythropoietin products. Evaluate any patient experiencing a loss of response to epoetin alfa to determine the etiology of the loss of effect. Discontinue epoetin alfa in any patient with evidence of PRCA, and evaluate the patient for the presence of binding and neutralizing antibodies to epoetin alfa, native erythropoietin, and any other recombinant erythropoietin administered to the patient. Contact the manufacturer to perform assays for binding and neutralizing antibodies. Neutralizing antibodies to erythropoietin, in association with PRCA or severe anemia (with or without other cytopenias), have been reported in patients receiving epoetin alfa. For the period of July 1997 through December 2001, 82 cases of PRCA after administration of epoetin alfa were reported to the FDA MedWatch program. Four patients received Epogen, none received Procrit, and 78 received Eprex, a product that is only distributed outside the US. The median age of patients with PRCA was 61 years, and 66% were men. The median duration of treatment with epoetin alfa to the time to diagnosis was 7 months (range: 1 month to 5 years). All patients received epoetin alfa for anemia associated with chronic renal failure. PRCA also has been reported in patients receiving erythropoiesis-stimulating agents undergoing treatment for hepatitis C with interferon and ribavirin. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Comparison of the incidence of antibodies across products within this class (erythropoietic proteins) may be misleading.

A higher incidence of cardiovascular adverse reactions and death have occurred in adult patients receiving epoetin alfa; however, the implications for pediatric patients are not known. Among adult patients with chronic kidney disease, those who received an erythropoiesis stimulating agent (ESA) to target a hemoglobin concentration more than 11 g/dL had greater risks for death, serious adverse cardiovascular reactions, and stroke. Unfortunately, no trial has identified a hemoglobin target concentration, ESA dose, or dosing strategy that does not increase these risks. In controlled clinical trials of adult patients with cancer, ESAs increased the risks for death and serious adverse cardiovascular reactions such as myocardial infarction and stroke. Furthermore, in patients with cancer, ESAs should only be used in those patients with anemia secondary to chemotherapy treatment, should not be used if the anticipated outcome of chemotherapy is cure, should not be initiated unless the hemoglobin is less than 10 g/dL, and should be dosed to achieve a hemoglobin concentration sufficient to avoid blood transfusions. In a trial of epoetin alfa in adult hemodialysis patients with cardiac disease, mortality was increased in the group randomized to a target hemoglobin of 14 g/dL vs. 10 g/dL. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic effects was also higher in the group randomized to achieve a hemoglobin of 14 g/dL. Furthermore, in a study of adult patients with renal impairment defined as chronic kidney disease not requiring renal replacement therapy (CrCl of 15 to 50 mL/minute/1.73 m2 of body surface area using the MDRD formula), a goal hemoglobin concentration of 13.5 g/dL (12.6 g/dL was the average concentration achieved during the study) vs. 11.3 g/dL was associated with an increased incidence of death, myocardial infarction, hospitalization for congestive heart failure without renal replacement therapy, and stroke. In patients with cancer, multiple clinical trials have shown negative survival and disease control outcomes in patients receiving ESAs. Among patients receiving chemotherapy alone for their disease, clinical trials conducted in patients with breast cancer (early and metastatic), cervical cancer, and lymphoid malignancies showed decreases in locoregional control, progression-free survival, and overall survival. In patients receiving radiation therapy alone, trials conducted in patients with head and neck cancer revealed decreases in locoregional control, 5-year locoregional progression-free survival, and overall survival. In patients not actively receiving treatment for their cancer, trials conducted in patients with non-small cell lung cancer and non-myeloid malignancies showed decreases in overall survival.

A higher incidence of thrombosis and other thrombotic events have occurred in adult patients receiving epoetin alfa; however, the implications for pediatric patients are not known. In a trial of epoetin alfa in adult hemodialysis patients with cardiac disease randomized to achieve a hemoglobin of 14 g/dL vs. 10 g/dL, the incidence of vascular access thrombosis and all other thrombotic events was higher in the group randomized to achieve a hemoglobin of 14 g/dL. In patients receiving an ESA, but not prophylactic anticoagulation, prior to surgical procedures in an effort to minimize the risk of allogeneic RBC transfusion, an increased incidence of venous thromboembolism has been noted in patients undergoing spinal surgery (deep venous thrombosis, DVT, incidence of 4.7% in patients receiving epoetin alfa vs. 2.1% in placebo). The incidence of DVT was 3% to 6% in patients undergoing major orthopedic surgery administered epoetin alfa compared to 3% in patients who received placebo. In patients receiving epoetin alfa to reduce the necessity of allogeneic RBC transfusion, antithrombotic prophylaxis is recommended. In zidovudine-treated HIV-infected patients, pulmonary embolism occurred in 1% of patients receiving epoetin alfa. Increased mortality has been demonstrated in patients receiving epoetin alfa prior to CABG surgery; the deaths were associated with a thromboembolic/vascular event. Illicit use of recombinant erythropoietin products by athletes, particularly cyclists, has led to a number of cases of sudden death. In these athletes, epoetin alfa caused a significant increase in hemoglobin concentrations that when exacerbated by dehydration during heavy exertion led to fatal thromboembolism. In addition, a systematic review of trials in patients with cancer (+/- chemotherapy) receiving ESAs versus placebo or standard of care found a significantly increased risk of thromboembolic events in patients receiving an ESA (RR 1.57, 95% CI 1.31 to 1.87) and a non-significant increase in mortality risk (RR 1.1, 95% CI 1.01 to 1.2).

An injection site reaction, described as irritation (7% vs. 4% placebo) and pain (9% to 13% vs. 8% placebo), has been reported with epoetin alfa. Phlebitis and/or thrombophlebitis at the IV infusion site can be a problem during intravenous epoetin alfa therapy. Vascular occlusion (vascular access thrombosis) was reported in 8.1% (vs. 2.1% placebo) of patients with chronic kidney disease on dialysis. Additionally, medical device malfunction (artificial kidney clotting during dialysis) occurred in 8.1% (vs. 4.2%) of patients with chronic kidney disease on dialysis. Clotting problems are attributed to increased blood viscosity and a slight rise in platelet count, along with a decrease in bleeding time.

Flu-like symptoms can occur during epoetin alfa therapy. Arthralgia was reported more frequently in patients receiving the drug compared to placebo (chronic kidney disease on dialysis 16.2% vs. 3.1%; chronic kidney disease not on dialysis 12.2% vs. 7.6%; and cancer 10% vs. 6%). Muscle spasm was reported in 7.4% (vs. 6.3%) of patients with chronic kidney disease on dialysis. Fever (pyrexia) was reported in patients with chronic kidney disease on dialysis (10.1% vs. 8.3%) and in zidovudine-treated HIV-infected patients (42% vs. 34%). Chills were reported in surgery patients (4% to 7% vs. 1%). Myalgia (10% vs. 5%) and bone pain (7% vs. 4%) were reported in cancer patients receiving epoetin alfa.

In cancer and surgery patients receiving epoetin alfa, nausea has been reported at rates of 35% to 56% (vs. 30% to 45% for placebo) and vomiting at rates of 12% to 28% (vs. 14% to 16%). Stomatitis (10% vs. 8%), weight loss (9% vs. 5%), and dysphagia (5% vs. 2%) were also reported in cancer patients receiving epoetin alfa.

Skin rash has been reported during epoetin alfa treatment in cancer patients (7% vs. 5% placebo) and surgery patients (2% to 3% vs. 1%). Pruritus was also reported in surgery patients (12% to 21% vs. 14%). Erythema (0.8% vs. 0%) was reported in patients with chronic kidney disease not on dialysis. In zidovudine-treated HIV-infected patients, skin rash (19% vs. 7%) and urticaria (3% vs. 1%) have been reported. Serious allergic reactions, including anaphylactoid reactions, angioedema, bronchospasm, skin rash, and urticaria may occur. In addition, blistering and skin exfoliation reactions including erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported. Discontinue epoetin alfa immediately if a severe cutaneous or allergic reaction is suspected and administer appropriate therapy. Do not re-initiate treatment in patients who experience serious allergic or anaphylactic reactions.

During placebo-controlled clinical trials of epoetin alfa, respiratory-related adverse reactions have been reported. Cough was reported in 4% to 9% of cancer or surgery patients (vs. 0% to 7% placebo) and in 26% of zidovudine-treated HIV patients (vs. 14%). Upper respiratory tract infection was reported in 6.8% of patients with chronic kidney disease on dialysis (vs. 5.2%). Respiratory congestion was reported in 1% of zidovudine-treated HIV patients.

During clinical trials of epoetin alfa in cancer patients, hypokalemia (5% vs. 3% placebo), hyperglycemia (6% vs. 4%), and leukopenia (8% vs. 7%) were reported. When epoetin alfa was used in surgery patients, edema occurred in 1% to 3% of patients compared to 2% of patients receiving placebo.

Porphyria has been reported with the postmarketing use of epoetin alfa.

Epoetin alfa is contraindicated in patients with serious allergic reactions to epoetin alfa, such as anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria. Immediately and permanently discontinue epoetin alfa and administer appropriate therapy if a hypersensitivity reaction occurs.

Epoetin alfa is contraindicated in patients with pure red cell aplasia (PRCA) that begins after treatment with epoetin or other erythropoietin protein drugs. Cases of PRCA and of severe anemia, with or without other cytopenias, associated with neutralizing antibodies to erythropoietin have been reported in patients treated with epoetin. PRCA has been reported predominantly in patients with chronic kidney failure receiving epoetin by subcutaneous administration. Evaluate any patient who develops a sudden loss of response to epoetin, accompanied by severe anemia and low reticulocyte count, for the etiology of loss of effect, including the presence of binding and neutralizing antibodies to erythropoietin. If anti-erythropoietin antibody-associated anemia is suspected, withhold epoetin and other erythropoietic proteins. Contact the manufacturer to perform assays for binding and neutralizing antibodies. Permanently discontinue epoetin in patients with antibody-mediated anemia. Patients should not be switched to other erythropoietic proteins as antibodies may cross-react.

In controlled trials, adult patients with chronic kidney disease (CKD) such as renal impairment or renal failure experienced greater risks for mortality, myocardial infarction, congestive heart failure, thromboembolism, and stroke when administered epoetin alfa and other erythropoiesis-stimulating agents (ESAs) to a target hemoglobin concentration greater than 11 g/dL. No trial has identified a hemoglobin target concentration, ESA dose, or dosing strategy that does not increase these risks. Use the lowest dose sufficient to reduce the need for red blood cell transfusions. For pediatric patients with CKD, initiate epoetin alfa treatment only when the hemoglobin concentration is less than 10 g/dL. Reduce or interrupt treatment if the hemoglobin concentration approaches or exceeds 12 g/dL. Use caution in patients with coexistent cardiac disease, stroke, and cardiovascular disease such as angina. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of more than 1 g/dL over 2 weeks may contribute to these risks; a dose reduction is warranted. During hemodialysis, patients treated with epoetin alfa may require increased anticoagulant therapy with heparin to prevent clotting of the dialysis machine.

Epoetin alfa is contraindicated in patients with uncontrolled hypertension; appropriately control hypertension prior to initiation of and during treatment with epoetin alfa in all patients. Reduce or withhold treatment if blood pressure becomes difficult to control. Up to 25% of adult patients on dialysis require initiation of, or increases in, antihypertensive therapy after initiation of epoetin alfa.

Epoetin alfa increases the risk of seizures in patients with chronic kidney disease (CKD); use with caution in patients with a preexisting seizure disorder. Monitor patients closely for premonitory neurologic symptoms during the first several months of treatment. Advise patients to contact their healthcare professional if new-onset seizures, premonitory symptoms, or change in seizure frequency occurs.

The majority of patients with chronic kidney disease will require iron supplementation during epoetin alfa therapy. Evaluate iron status, including transferrin saturation and serum ferritin, before and during treatment and maintain iron repletion. Administer supplemental iron therapy when transferrin saturation is less than 20% or serum ferritin is less than 100 ng/mL. For lack or loss of hemoglobin response to epoetin alfa, evaluate for causative factors, including iron-deficiency anemia.

Conditions that may interfere with response to epoetin alfa include bleeding, infection, inflammation, malignancy, malnutrition, hypothyroidism, hyperparathyroidism, vitamin B12 deficiency, folate deficiency, hematological disease (e.g., hemolytic anemia, sickle cell disease, thalassemia, refractory anemia), and bone marrow disorders, such as myelodysplastic syndrome (MDS). Evaluate for the cause of a lack of a hemoglobin response or failure to maintain a hemoglobin response with darbepoetin alfa. If possible, correct the etiology such as vitamin B12 or folate deficiency. In the absence of another etiology, evaluate for pure red cell aplasia (PRCA), including testing for the presence of antibodies to erythropoietin. In persons in whom all correctable causes have been maximally treated but who remain hyporesponsive, erythropoietin-stimulating agent therapy may be continued cautiously at doses up to 4 times the initial dose to prevent a further decline in hemoglobin concentration. Red blood cell transfusions can be used to prevent or treat anemia-related symptoms and signs.

Epoetin alfa (Epogen, Procrit) should be used with caution in patients with known albumin hypersensitivity. Due to effective plasma donor screening for prior exposure to certain viruses, testing for the presence of viruses, and manufacturing processes designed to reduce the risk of transmitting viral infection, the risk of transmission of infectious agents associated with epoetin alfa products formulated with albumin is remote. However, none of the processes are completely effective. There is also the possibility that unknown infectious agents may be present. A theoretical risk of the transmission of Creutzfeldt-Jakob disease (CJD) is also considered remote. No cases of transmission of viral infections or CJD have ever been identified for albumin.

Use only the single-dose vials of epoetin alfa in neonates and infants. The multidose vials of epoetin alfa contain benzyl alcohol and are contraindicated in neonates, infants, and patients with benzyl alcohol hypersensitivity. Do not mix the single-dose vial with bacteriostatic saline, which also contains benzyl alcohol, when administered to these patient populations. There have been reports of fatal "gasping syndrome" in neonates after the administration of parenteral solutions containing the preservative benzyl alcohol at dosages more than 99 mg/kg/day. This syndrome is characterized by central nervous depression, metabolic acidosis, and gasping respirations. The minimum amount of benzyl alcohol necessary to cause toxicity is unknown. In utero exposure to benzyl alcohol or exposure via breast milk could potentially put the child at risk; hence, multidose vials are also contraindicated in pregnant and lactating women.

Use of epoetin alfa and other erythropoiesis stimulating agents (ESAs) shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with certain neoplastic disease: breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. ESAs are not indicated for patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. In addition, ESAs are not indicated for patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion. In patients with cancer, use ESAs only for anemia from myelosuppressive chemotherapy, and use the lowest dose needed to avoid red blood cell transfusions. Use of the lowest dose to avoid red blood cell transfusions will also help to decrease the risk of serious cardiovascular and thromboembolic reactions. In controlled clinical trials of patients with cancer, ESAs increased the risks for death and serious adverse cardiovascular reactions such as myocardial infarction and stroke. Discontinue the ESA after the completion of a chemotherapy course.

In controlled clinical trials, erythropoiesis-stimulating agents (ESAs) increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of thromboembolism (deep venous thrombosis [DVT]) in patients undergoing orthopedic procedures. While CABG is not a typical procedure in pediatric patients, the exact risk factor for these adverse events is not clear; possible implications in pediatric patients, particularly those undergoing other types of cardiac surgery, are not known. Epoetin alfa is not indicated for use in patients undergoing cardiac or vascular surgery and should not be used in patients scheduled for surgery who are willing to donate autologous blood. Weigh the anticipated benefits of epoetin alfa in any patient with a history of thromboembolic disease against the potential risks; the risk of thromboembolism is increased in many populations. Due to increased risk of DVT, prophylaxis is strongly recommended when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients.

Retacrit contains phenylalanine, a component of aspartame. In patients with phenylketonuria, consider the combined daily amount of phenylalanine from all sources. Each single-dose vial of Retacrit contains 0.5 mg of phenylalanine.

Description: Epoetin alfa (r-HuEPO) is a recombinant form of the renal hormone erythropoietin (EPO) and belongs to a class of drugs known as erythropoiesis-stimulating agents (ESAs). Native EPO is a glycosylated protein with a molecular weight of about 36,000 daltons. Epoetin alfa is produced via recombinant technology in a Chinese hamster ovarian cell system. It is immunologically and biologically indistinguishable from native EPO, and its structure is very similar to the native protein with a molecular weight of 30,400 daltons. Epoetin alfa is FDA-approved for the treatment of anemia in chronic renal failure patients, zidovudine-treated HIV patients, in patients receiving cancer chemotherapy, and to reduce the need for allogeneic blood transfusions in surgery patients. It has been used off-label in premature neonates with anemia of prematurity and for neuroprotection in term neonates with hypoxic-ischemic encephalopathy. Since less than 2% of the dose crosses the blood-brain barrier, higher doses and a shorter duration of treatment is used for neuroprotection. In adult patients, ESAs have been shown to increase the risk of death, myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access, and tumor progression or recurrence. ESAs are not indicated for use in patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Clinicians are advised to use the lowest dose that will gradually increase the hemoglobin concentration to the lowest hemoglobin sufficient to avoid the need for RBC transfusions. Epoetin alfa is FDA-approved in pediatric patients as young as 1 month of age.

General dosing information:
-Evaluate the iron status in all patients before and during treatment. Administer supplemental iron when the serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%; maintain iron repletion during epoetin alfa therapy.
-Correct or exclude other causes of anemia such as vitamin deficiency, metabolic or chronic inflammatory conditions, and bleeding before initiating epoetin alfa. Monitor hemoglobin weekly until stable and sufficient to minimize the need for red blood cell (RBC) transfusions.
-Epoetin alfa has not been shown to improve quality of life, fatigue, or patient well-being.
-Epoetin alfa is not indicated for use:-In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
-In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
-In patients with cancer receiving myelosuppressive chemotherapy in whom anemia can be managed by transfusion.
-In patients scheduled for surgery who are willing to donate autologous blood.
-In patients undergoing cardiac or vascular surgery.
-As a substitute for RBC transfusions in patients who require immediate correction of anemia.

-Use only single-dose (i.e., benzyl alcohol-free) vials in neonates and infants.

Dosage Conversion Information:
Darbepoetin alfa differs from epoetin alfa by the addition of 2 carbohydrate chains, resulting in different dosing regimens. There is no agreement regarding appropriate dosage conversion guidelines to achieve a similar clinical effect. The manufacturers have suggested a conversion ratio of epoetin alfa to darbepoetin alfa of 400:1 at a minimum, and no greater than 254:1. The US Federal Government has performed its own review and has determined the following ratio for use in Medicare payments: 260 units of epoetin alfa to 1 mcg darbepoetin alfa (260:1).

For the treatment of anemia:
-for anemia due to chronic kidney disease to decrease the need for red blood cell transfusion:
NOTE: Epoetin alfa has been designated an orphan drug by the FDA for this indication.
Subcutaneous or Intravenous dosage:
Infants, Children, and Adolescents 1 month to 16 years: 50 units/kg/dose IV or subcutaneously 3 times weekly initially; for patients on dialysis, administer IV. Initiate treatment when hemoglobin (Hgb) is less than 10 g/dL. If Hgb approaches or exceeds 12 g/dL, reduce or interrupt the dose. If the Hgb rises more than 1 g/dL in any 2-week period, reduce the dose by 25% or more as needed to reduce rapid responses. In contrast, if Hgb has not increased more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%. Do not increase the dose more frequently than once every 4 weeks; decreases can occur more frequently. For patients who do not respond adequately over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a Hgb concentration sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia, and discontinue if responsiveness does not improve.
Adolescents 17 years: 50 to 100 units/kg/dose IV or subcutaneously 3 times weekly initially; for patients on dialysis, administer IV. For patients on dialysis, initiate treatment when hemoglobin (Hgb) is less than 10 g/dL. If Hgb approaches or exceeds 11 g/dL, reduce or interrupt the dose. For patients not on dialysis, consider initiating treatment only when Hgb is less than 10 g/dL and the rate of Hgb decline indicates the likelihood of requiring a RBC transfusion and reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal. If Hgb is more than 10 g/dL, reduce or interrupt the dose, and use the lowest dose sufficient to reduce the need for RBC transfusions. If the Hgb rises more than 1 g/dL in any 2-week period, reduce the dose by 25% or more as needed to reduce rapid responses. In contrast, if Hgb has not increased more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%. Do not increase the dose more frequently than once every 4 weeks; decreases can occur more frequently. For patients who do not respond adequately over a 12-week escalation period, increasing the dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a Hgb concentration sufficient to reduce the need for RBC transfusions. Evaluate other causes of anemia, and discontinue if responsiveness does not improve.
-for zidovudine-induced anemia in HIV-infected patients with circulating endogenous erythropoietin concentrations 500 mUnits/mL or less:
NOTE: Epoetin alfa has been designated an orphan drug by the FDA for this indication.
Subcutaneous and Intravenous dosage:
Infants*, Children*, and Adolescents* 8 months to 17 years: A limited number of pediatric HIV-infected patients have been treated with epoetin alfa 50 to 400 units/kg/dose subcutaneously or IV 2 to 3 times per week. If the Hgb is more than 12 g/dL, withhold epoetin and once Hgb is less than 11 g/dL, resume at a dose 25% below the previous dose. Patients receiving zidovudine with endogenous serum erythropoietin concentrations more than 500 mUnits/mL are unlikely to respond to epoetin alfa treatment.
-for anemia in patients with non-myeloid malignancies where the anemia is due to the effect of concomitantly administered chemotherapy and at least 2 additional months of chemotherapy is planned:
Subcutaneous and Intravenous dosage:
Children and Adolescents 5 to 17 years: 600 units/kg/dose IV weekly only when the hemoglobin is less than 10 g/dL and only until the chemotherapy course is completed. Adjust the dose to maintain the lowest Hgb concentration sufficient to avoid RBC transfusions. If no rise in Hgb of at least 1 g/dL after 4 weeks of therapy and Hgb is less than 10 g/dL, the dosage may be increased to 900 units/kg/dose IV weekly (Max: 60,000 units). Discontinue if after 8 weeks there is no response as measured by Hgb concentrations or if transfusions are still required. Reduce the dose by 25% if Hgb increases by more than 1 g/dL in any 2-week period or if Hgb reaches a concentration needed to avoid RBC infusion. If the Hgb is increasing and exceeds a concentration necessary to avoid blood transfusions, hold therapy and reinstitute at a dose that is 25% lower when the Hgb reaches a concentration where transfusions may be needed.
-for anemia of prematurity*, in combination with iron supplementation:
Subcutaneous and Intravenous dosage:
Premature neonates: Various dosing regimens have been used in studies. Total weekly doses of 75 to 1,500 units/kg/week subcutaneously or IV divided into 3 to 7 doses for a total duration of 10 days to 6 weeks have been administered to premature neonates. The most commonly studied dosing regimen is 200 to 250 units/kg/dose subcutaneously or IV given 3 times weekly for up to 6 weeks. Oral iron 2 to 9 mg/kg/day was also administered in most studies.

For the treatment of hypoxic-ischemic encephalopathy (HIE)*:
Subcutaneous and Intravenous dosage:
NOTE: Epoetin alfa has been designated an orphan drug by the FDA for this indication.
Neonates: Optimal regimen and place in therapy have not been defined; doses ranging from 300 to 2,500 units/kg/dose IV have been given daily or every other day for a short duration after birth. In a study of 167 term neonates with moderate to severe HIE, the use of erythropoietin (300 or 500 units/kg/dose every other day for 2 weeks beginning less than 48 hours after birth) resulted in improved neurological outcomes in patients with moderate (but not severe) HIE compared to conventional treatment (no erythropoietin). At 18 months of age, fewer patients in the erythropoietin group had experienced death or moderate/severe disability compared to the control group (24.6% vs. 43.8%, respectively; p = 0.017); neonates in the erythropoietin group also had fewer hospitalizations during the study period. No difference was found between the erythropoietin doses. In a prospective case-control study, the administration of erythropoietin 2,500 units/kg/dose subcutaneously for 5 days to neonates with mild/moderate HIE (n = 15) was associated with fewer neurologic and developmental abnormalities at 6 months of age compared to conventional therapy (no erythropoietin; n = 15). Erythropoietin was well tolerated.

Therapeutic Drug Monitoring:
-In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin concentration more than 11 g/dL. No trial has identified a hemoglobin target concentration, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose sufficient to reduce the need for red blood cell (RBC) transfusions. Weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse reactions.
-When initiating or adjusting therapy, monitor hemoglobin weekly until stable and sufficient to minimize the need for RBC transfusion, then monitor at least monthly.
-For all patients with chronic renal failure, avoid frequent dose adjustments. Do not increase the dose more frequently than once every 4 weeks; decreases can occur more frequently. When adjusting therapy, consider rate of hemoglobin rise, rate of decline, ESA responsiveness, and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
-If a patient fails to respond to or maintain a response to therapy, evaluate the cause of decreased or lack of response.

Maximum Dosage Limits:
-Neonates
Safety and efficacy have not been established; however, doses up to 2,500 units/kg/dose subcutaneously/IV have been used off-label for hypoxic-ischemic encephalopathy.
-Infants
1 to 7 months: Varies depending upon indication, frequency of administration, and individual response.
8 to 11 months: Varies depending upon indication, frequency of administration, and individual response; a limited number of HIV-infected infants have been treated off-label with doses up to 400 units/kg/dose subcutaneously/IV 3 times per week.
-Children
1 to 4 years: Varies depending upon indication, frequency of administration, and individual response; a limited number of HIV-infected children have been treated off-label with doses up to 400 units/kg/dose subcutaneously/IV 3 times per week.
5 to 12 years: Varies depending upon indication, frequency of administration, and individual response. For patients with cancer, 900 units/kg/week IV (Max: 60,000 units) until completion of chemotherapy. A limited number of HIV-infected children have been treated off-label with doses up to 400 units/kg/dose subcutaneously/IV 3 times per week.
-Adolescents
Varies depending upon indication, frequency of administration, and individual response. For patients with cancer, 900 units/kg/week IV (Max: 60,000 units) until completion of chemotherapy. A limited number of HIV-infected adolescents have been treated off-label with doses up to 400 units/kg/dose subcutaneously/IV 3 times per week.

Patients with Hepatic Impairment Dosing
Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Patients with Renal Impairment Dosing
No dosage adjustment needed.

*non-FDA-approved indication

Monograph content under development

Mechanism of Action: Erythropoietin (EPO) is a glycoprotein that regulates the production of red blood cells by stimulating the division and differentiation of committed erythroid progenitor cells in the bone marrow. Epoetin alfa has the same biological activity as native EPO. In adults, almost 90% of EPO is produced in the kidney with the remainder produced by the liver. During fetal development, EPO is produced in the liver, and prior to birth at term, production is transferred to the kidney. Erythropoietin production in the kidney occurs in interstitial cells in the inner cortex that are in immediate proximity to the proximal tubules. More cells are activated as the hematocrit drops. Renal tubular cells may serve as oxygen sensors transmitting signals to the interstitial cells, possibly because they contain large amounts of heme protein that may function as an intracellular oxygen sensor and transducer.

Erythropoietin is required for the transformation of the most mature erythroid progenitor cell, erythroid colony-forming unit (CFU-E), to a proerythroblast. In the absence of EPO, this transformation cannot occur and the CFU-E will die. Erythropoietin activates the synthesis of hemoglobin and other proteins found in normal erythroblasts. Erythropoietin also causes a shift of marrow reticulocytes into the circulation. Due to the length of time required for erythropoiesis, a clinically significant increase in hematocrit is usually not observed in less than 2 weeks and may take up to 6 weeks in some patients. Erythropoietin has little effect on early erythroid progenitor cells, erythroid burst-forming units (BFU-E), whose growth is more dependent upon interleukin-3 and granulocyte-macrophage colony stimulating factor (GM-CSF). The production and activity of EPO is linked in a negative feedback loop, which maintains optimal red cell mass for oxygen transport. There appears to be a plateau of optimal oxygen transport to tissues occurring around hematocrits of 35% to 55% with significant decreases in oxygen transport above and below these values. Epoetin alfa produces a dose-dependent increase in the hematocrit; an increase of 2% per week may be seen during the initial phase of therapy. The stimulation of erythropoiesis increases the demand for iron, making iron supplementation necessary for many patients.

Pharmacokinetics: Epoetin alfa is administered intravenously or subcutaneously. A dose-dependent response is seen with epoetin alfa doses of 50 to 300 units/kg/dose 3 times a week; however, a greater response is not seen at doses more than 300 units/kg/dose 3 times a week. Other factors affecting response to therapy include iron stores, baseline hematocrit, and concurrent medical conditions. As with the endogenous erythropoietin (EPO), epoetin alfa does not appear extravascularly in humans. Metabolism and elimination of endogenous EPO or epoetin alfa are not fully understood. While the glycosylation of EPO does not affect its binding to target cells, it plays an important role in preventing the rapid clearance of the hormone from the bloodstream. Non-glycosylated erythropoietin has a half-life in vivo of a few minutes. About 10% of the dose appears to be excreted in the urine. In healthy volunteers, the half-life of epoetin alfa is approximately 20% shorter than the half-life in patients with chronic renal failure.

Affected cytochrome P450 isoenzymes: none


-Route-Specific Pharmacokinetics
Intravenous Route
Administering epoetin alfa by the IV route results in a more rapid peak; however, the delayed systemic absorption from the subcutaneous route gives a more sustained response.

Subcutaneous Route
The subcutaneous route of administration produces peak plasma concentrations between 5 to 24 hours after the dose. Although the IV route gives a more rapid peak, the delayed systemic absorption from the subcutaneous route gives a more sustained response. Subcutaneous administration can result in some drug accumulation because of delayed absorption.


-Special Populations
Pediatrics
Premature neonates
Relative to data obtained in 10 healthy adults, a study of 7 very low birthweight neonates given IV erythropoietin suggests that the volume of distribution and clearance are higher (1.5 to 2-fold and 3-fold, respectively) in premature neonates. In a pharmacokinetic study performed in 40 preterm neonates (weight 750 grams to 1.25 kg, younger than 72 hours of age), patients were randomly assigned to receive epoetin alpha 200 units/kg/day subcutaneously or it was added to their TPN fluids daily. In the neonates who received epoetin alpha subcutaneously, the elimination half-life was 17.6 +/- 4.4 hours on day 3 and 11.2 +/-1.5 hours on day 10; the volume of distribution was 802 +/- 190 mL/kg on day 3 and 1,330 +/- 243 mL/kg on day 10. For both groups, serum epoetin concentrations were higher on day 3 than on day 10 (subcutaneous: 400 +/- 64 milliunits/mL vs. 177 +/- 29 milliunits/mL; TPN: 395 +/- 64 vs. 194 +/- 41 milliunits/mL). Clearance did not differ between the 2 groups with regard to route of administration and increased significantly from days 3 to 10 in both groups (subcutaneous: 35 +/- 5 mL/kg/hour at day 3 and 87 +/- 16 mL/kg/hour at day 7; TPN: 26 +/- 4 mL/kg/hour at day 3 and 65 +/- 20 mL/kg/hour at day 7).

In a prospective, dose-escalation, open-label trial, 60 premature neonates (younger than 24 hours old, weighing 1 kg or less, 28 weeks gestational age or younger) were treated with either high-dose recombinant erythropoietin or a control. Each neonate received 3 intravenous doses of 500, 1,000, or 2,500 units/kg at 24-hour intervals beginning on day 1 of age. The relationship between AUC and dosage was nonlinear. Epoetin alfa exhibited nonlinear pharmacokinetics since clearance decreased with increasing dosage (17.3 mL/kg/hour for 500 units/kg) to the highest dosage (8.2 mL/kg/hour for 2,500 units/kg). The mean AUC ratios were 2.6 for the 1,000 units/kg and 500 units/kg dosages and 10.1 for the 2,500 units/kg and 500 unit/kg dosages. Distribution volumes did not change as dosage increased. Steady-state plasma epoetin alpha concentrations were attained by the second dose for all 3 dosages. Both 1,000 and 2,500 units/kg recombinant erythropoietin produced peak serum erythropoietin concentrations that were comparable to neuroprotective concentrations previously seen in experimental animals.

Children and Adolescents
The pharmacokinetic profile of epoetin alfa in children and adolescents appears to be similar to that of adults.

Hepatic Impairment
The disposition of epoetin alfa in patients with hepatic impairment has not been studied.

Renal Impairment
Epoetin alfa half-life in pediatric and adult patients with chronic renal failure after IV administration is 4 to 13 hours. The drug is not removed by hemodialysis.