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    Erythropoietin Agents

    BOXED WARNING

    Angina, anticoagulant therapy, cardiac disease, dialysis, heart failure, hemoglobin concentration greater than 11 g/dl, mortality, myocardial infarction, renal failure, renal impairment, stroke

    In controlled trials, 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 patients with CKD either on or off dialysis, a hemoglobin less than 10 g/dL is advised before treatment initiation. 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.

    Coronary artery bypass graft surgery (CABG), surgery, thromboembolism

    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. 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 red blood cell transfusions in surgical patients.

    Neoplastic disease

    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.

    DEA CLASS

    Rx

    DESCRIPTION

    Recombinant form of the renal hormone erythropoietin
    Used for treatment of anemia and for reduction of allogeneic red blood cell transfusions in surgical patients
    Associated with increased risk of death, myocardial infarction, stroke, venous thromboembolism, vascular access thrombosis, and tumor progression or recurrence

    COMMON BRAND NAMES

    Epogen, Procrit, Retacrit

    HOW SUPPLIED

    Epogen/Procrit/Retacrit Intravenous Inj Sol: 1mL, 2000U, 3000U, 4000U, 10000U, 20000U, 40000U
    Epogen/Procrit/Retacrit Subcutaneous Inj Sol: 1mL, 2000U, 3000U, 4000U, 10000U, 20000U, 40000U

    DOSAGE & INDICATIONS

    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
    Adults

    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.

    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.

    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.

    For zidovudine-induced anemia in HIV-infected patients with circulating endogenous erythropoietin concentrations of 500 mUnits/mL or less who are receiving a dose of zidovudine of 4,200 mg/week or less.
    NOTE: Epoetin alfa has been designated an orphan drug by the FDA for this indication.
    Subcutaneous and Intravenous dosage
    Adults

    Initially, 100 units/kg/dose subcutaneously or IV 3 times weekly. If Hgb does not increase after 8 weeks, increase by 50 to 100 units/kg/dose at 4 to 8 week intervals until Hgb is at a concentration to avoid RBC transfusions or a dose of 300 units/kg is reached. 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 levels more than 500 mUnits/mL are unlikely to respond to epoetin alfa treatment.

    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 levels 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
    Adults

    150 units/kg/dose subcutaneously 3 times weekly or 40,000 units subcutaneously once weekly only when the hemoglobin (Hgb) 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 300 units/kg/dose subcutaneously 3 times weekly or 60,000 units subcutaneously once weekly. Discontinue if after 8 weeks of therapy 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 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.

    Children and Adolescents 5 to 17 years

    600 units/kg/dose IV weekly only when the hemoglobin (Hgb) 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.

    To reduce the need for allogeneic red blood cell transfusions in patients with perioperative hemoglobin more than 10 g/dL to 13 g/dL scheduled to undergo elective, noncardiac, nonvascular surgery who are at high risk for perioperative blood loss and who are NOT willing to donate autologous blood preoperatively.
    Subcutaneous dosage
    Adults

    300 units/kg/day subcutaneously for 10 days before surgery, on the day of surgery, and for 4 days after surgery (15 days total) plus deep vein thrombosis (DVT) prophylaxis. Alternatively, 600 units/kg/dose subcutaneously on days 21, 14, and 7 before surgery plus 1 dose on the day of surgery (4 total doses) plus DVT prophylaxis.

    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 anemia associated with myelodysplastic syndrome† (MDS).
    NOTE: Epoetin alfa has been designated an orphan drug by the FDA for this indication.
    Subcutaneous dosage
    Adults

    150 to 300 units/kg/dose subcutaneously 3 times weekly has been shown to improve anemia in about 20% of patients with MDS. When epoetin alfa is given in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) or granulocyte colony stimulating factor (G-CSF), response increases to about 50% of MDS patients.

    For anemia secondary to combination ribavirin and interferon-alfa therapy in patients infected with hepatitis C virus†.
    Subcutaneous dosage
    Adults

    40,000 units subcutaneously once weekly maintained the ribavirin dose in anemic patients with chronic hepatitis C virus. After 4 weeks, if the hemoglobin (Hgb) had not increased by at least 1 g/dL, the weekly dose was increased to 60,000 units subcutaneously. Patients with Hgb of 12 g/dL or less who were being treated with ribavirin and interferon alfa were randomized to receive epoetin alfa (n = 93) or placebo (n = 92) for 8 weeks. The ribavirin dose was maintained in 88% of patients receiving epoetin alfa compared to 60% of patients receiving placebo (p less than 0.001). At randomization, the baseline Hgb was 10.8 g/dL; after 8 weeks of treatment, Hgb increased by an average of 2.2 +/- 1.3 g/dL in the epoetin group compared to 0.1 +/- 1.0 g/dL in the placebo group (p less than 0.001).

    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.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Varies depending on indication, frequency of administration, and individual response; for patients with cancer, doses up to 60,000 units IV weekly until completion of chemotherapy.

    Geriatric

    Varies depending on indication, frequency of administration, and individual response; for patients with cancer, doses up to 60,000 units IV weekly until completion of chemotherapy.

    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.

    Children

    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.
    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.

    Infants

    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.
    1 to 7 months: Varies depending upon indication, frequency of administration, and individual response.

    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.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

    Renal Impairment

    No dosage adjustment needed.

    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.
    Discard unused epoetin alfa in preservative-free vials; do not re-enter preservative-free vials. Multi-dose vials with preservatives are available.
    Do not dilute. Do not administer with other drug solutions except as described below:
    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: Multi-dose 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.

    STORAGE

    Epogen:
    - Discard if product has been frozen
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    Procrit:
    - Discard if product has been frozen
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Discard unused portion. Do not store for later use.
    - Protect from freezing
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - Store in carton until time of use
    Retacrit:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Do not use if product has been frozen
    - Protect from light
    - Store between 36 to 46 degrees F
    - Store in carton until time of use

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

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

    Red cell aplasia

    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.

    Angina, anticoagulant therapy, cardiac disease, dialysis, heart failure, hemoglobin concentration greater than 11 g/dl, mortality, myocardial infarction, renal failure, renal impairment, stroke

    In controlled trials, 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 patients with CKD either on or off dialysis, a hemoglobin less than 10 g/dL is advised before treatment initiation. 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.

    Hypertension

    Epoetin alfa is contraindicated for use by patients with uncontrolled hypertension; control hypertension before and during epoetin alfa therapy in all patients. Reduce or withhold epoetin alfa if blood pressure becomes difficult to control. Advise patients about the importance of compliance with antihypertensive therapy and dietary restrictions. During the early phase of epoetin alfa therapy in patients with chronic kidney disease, approximately 25% of patients require initiation of or intensification of antihypertensive therapy.

    Seizure disorder, seizures

    In patients with chronic kidney disease, epoetin alfa increases the risk of seizures. During the first several months after epoetin alfa initiation, closely monitor patients for premonitory neurologic symptoms. Advise patients to contact their healthcare provider for new-onset seizures or premonitory symptoms, or in patients with history of seizure disorder, a change in seizure frequency.

    Coronary artery bypass graft surgery (CABG), surgery, thromboembolism

    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. 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 red blood cell transfusions in surgical patients.

    Iron-deficiency anemia

    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, in all patients before and during epoetin alfa therapy and maintain iron repletion. Administer supplemental iron therapy when serum transferrin saturation is less than 20% or serum ferritin is less than 100 mcg/L. For lack or loss of hemoglobin response to epoetin alfa, evaluate for causative factors, including iron-deficiency anemia.

    Folate deficiency, hematological disease, infection, vitamin B12 deficiency

    The following conditions can interfere with the response to epoetin alfa: acute or chronic infection or inflammation, aluminum overload, folate deficiency, hematological disease (e.g., thalassemia, refractory anemia, or other myelodysplastic disorder), occult blood loss, osteitis fibrosa cystica, or vitamin B12 deficiency. Responsiveness is usually restored upon resolution of the underlying problem. In pediatric patients on CAPD, peritonitis may exert a protracted suppressive effect on the response to epoetin. An elevated C-reactive protein concentration, often associated with inflammation and/or infection, has been a predictor of resistance to epoetin. Aluminum overload can prolong the treatment time required to reach the target hemoglobin/hematocrit or may require higher epoetin doses, but has not been shown to cause absolute resistance to therapy. Chronic blood loss results in iron deficiency and impaired epoetin response. Blood loss should be considered in patients who require increasing doses of epoetin to maintain a stable hemoglobin/hematocrit, in patients whose hemoglobin/hematocrit concentrations are falling, and in patients whose iron stores are not sustained with repetitive IV iron loading. Osteitis fibrosa impairs response to epoetin by replacing active marrow erythroid elements with fibrosis. There is a direct relationship between the degree of fibrosis and the amount of epoetin needed to maintain a stable hematocrit. Patients with sickle cell disease have a poor response to epoetin therapy and both alpha and beta thalassemia may respond poorly to epoetin. When treating alpha thalassemia with epoetin, hemoglobin may increase slowly, with therapy usually requiring very high doses over a long period. Folic acid and vitamin B12 are essential for optimal hemoglobin synthesis. Although concomitant vitamin B12 and folate supplementation is not required during epoetin administration, investigation into cofactor adequacy is recommended. Reversal of potentially treatable causes of resistance is the goal. When the cause of epoetin resistance is untreatable, either progressively increase the epoetin dose in an attempt to reach or maintain the target hemoglobin/hematocrit, transfuse with red blood cells, or accept a hemoglobin/hematocrit below the target concentration.

    Pregnancy

    Multidose vials of epoetin alfa are contraindicated during pregnancy due to the use of benzyl alcohol as a preservative. When epoetin alfa therapy is needed during pregnancy, use a single-dose vial, which is benzyl alcohol-free. Consider the benefits and risks of epoetin alfa single-dose vials for the mother and possible risks to the fetus when prescribing epoetin alfa to a pregnant woman. The limited available data on epoetin alfa use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. There are reports of intrauterine growth restriction and polyhydramnios in women with chronic renal disease, which is associated with an increased risk for these adverse pregnancy outcomes. In animal reproductive and developmental toxicity studies, embryofetal death, skeletal anomalies, and growth defects occurred when pregnant rats received epoetin alfa at doses approximating the clinical recommended starting doses.

    Breast-feeding

    Multidose vials of epoetin alfa are contraindicated in breast-feeding due to the use of benzyl alcohol as a preservative. Advise breast-feeding women to not breast-feed for at least 2 weeks after the last dose of epoetin alfa, if a multidose vial was used. Do not mix epoetin alfa with bacteriostatic saline containing benzyl alcohol. Use caution when administering epoetin alfa from a single-dose vial to a breast-feeding woman. There is no information regarding the presence of epoetin alfa in human milk, the effects on the breast-fed infant, or the effects on milk production. Endogenous erythropoietin is present in human milk.

    Benzyl alcohol hypersensitivity, infants, neonates

    Use only the single-dose vials of epoetin in neonates and infants. The multiple-dose vial of epoetin alfa contains benzyl alcohol and is contraindicated in neonates, infants, and patients with benzyl alcohol hypersensitivity. In addition, the single-dose vial should not be mixed 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; Epogen and Procrit multiple-dose vials contain 11 mg of benzyl alcohol per mL.

    Neoplastic disease

    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.

    Geriatric

    The federal Omnibus Budget Reconciliation Act (OBRA) regulates medication use in residents (e.g., geriatric adults) of long-term care facilities (LTCFs). According to the OBRA guidelines, assessment of causes and categories of anemia should precede or accompany use of an erythropoiesis stimulant such as epoetin alfa. Use must be monitored according to individual manufacturer instructions, including blood pressure, baseline serum iron or ferritin levels, and frequent complete blood count (CBC) to permit tapering or discontinuation when hemoglobin/hematocrit reaches or exceeds target ranges. Erythropoiesis stimulants may cause or worsen hypertension, and excess doses or duration can lead to polycythemia or serious thrombotic events (e.g., myocardial infarction, stroke).

    Albumin hypersensitivity, viral infection

    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.

    Phenylketonuria

    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.

    ADVERSE REACTIONS

    Severe

    pulmonary embolism / Delayed / 1.0-1.0
    seizures / Delayed / Incidence not known
    red cell aplasia / Delayed / Incidence not known
    heart failure / Delayed / Incidence not known
    myocardial infarction / Delayed / Incidence not known
    stroke / Early / Incidence not known
    thromboembolism / Delayed / Incidence not known
    thrombosis / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    toxic epidermal necrolysis / Delayed / Incidence not known
    bronchospasm / Rapid / Incidence not known
    anaphylactoid reactions / Rapid / Incidence not known
    porphyria / Delayed / Incidence not known

    Moderate

    hypertension / Early / 3.0-27.7
    stomatitis / Delayed / 10.0-10.0
    leukopenia / Delayed / 8.0-8.0
    bone pain / Delayed / 7.0-7.0
    hyperglycemia / Delayed / 6.0-6.0
    depression / Delayed / 5.0-5.0
    dysphagia / Delayed / 5.0-5.0
    hypokalemia / Delayed / 5.0-5.0
    edema / Delayed / 1.0-3.0
    erythema / Early / 0.8-0.8
    encephalopathy / Delayed / Incidence not known
    antibody formation / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    phlebitis / Rapid / Incidence not known

    Mild

    nausea / Early / 35.0-56.0
    fever / Early / 10.1-42.0
    vomiting / Early / 12.0-28.0
    cough / Delayed / 4.0-26.0
    pruritus / Rapid / 12.0-21.0
    rash / Early / 2.0-19.0
    headache / Early / 5.0-18.0
    arthralgia / Delayed / 10.0-16.2
    injection site reaction / Rapid / 7.0-13.0
    myalgia / Early / 10.0-10.0
    dizziness / Early / 9.5-9.5
    weight loss / Delayed / 9.0-9.0
    chills / Rapid / 4.0-7.0
    insomnia / Early / 6.0-6.0
    urticaria / Rapid / 3.0-3.0
    infection / Delayed / Incidence not known
    vitamin B6 deficiency / Delayed / Incidence not known

    DRUG INTERACTIONS

    Androgens: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Danazol: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Esterified Estrogens; Methyltestosterone: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Ferric carboxymaltose: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Ferumoxytol: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Fluoxymesterone: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Iron - Injectable Only: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Iron Dextran: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Iron Salts: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Iron Sucrose, Sucroferric Oxyhydroxide: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Iron: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Lenalidomide: (Moderate) Concomitant use of lenalidomide with erythropoietic agents such as epoetin alfa and darbepoetin alfa may increase the risk of thrombosis in patients with multiple myeloma patients who are also receiving dexamethasone. Use lenalidomide and erythropoietic agents with caution in these patients. Monitor for signs of thromboembolism (e.g., deep vein thrombosis, pulmonary embolism, myocardial infarction, stroke) and encourage patients to report symptoms such as shortness of breath, chest pain, or arm or leg swelling.
    Methyltestosterone: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Nandrolone Decanoate: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Oxandrolone: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Oxymetholone: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Polysaccharide-Iron Complex: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Prasterone, Dehydroepiandrosterone, DHEA (Dietary Supplements): (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Prasterone, Dehydroepiandrosterone, DHEA (FDA-approved): (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Sodium Ferric Gluconate Complex; ferric pyrophosphate citrate: (Minor) Inadequate iron stores will interfere with the therapeutic response to epoetin alfa (e.g., red blood cell production). Most patients with chronic kidney disease will require supplemental iron (e.g., iron dextran; iron salts; iron sucrose, sucroferric oxyhydroxide; polysaccharide-iron complex; sodium ferric gluconate complex) during epoetin alfa receipt. Evaluate transferrin saturation and serum ferritin before and during epoetin alfa treatment. Administer supplemental iron therapy when serum ferritin is < 100 mcg/L or when serum transferrin saturation is < 20%. After initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin concentration is stable and sufficient to minimize the need for RBC transfusion.
    Testolactone: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Testosterone: (Moderate) Androgens are known to stimulate erythropoiesis. Concurrent administration of androgens can increase the patient's response to epoetin alfa, reducing the amount required to treat anemia. Because adverse reactions have been associated with an abrupt increase in blood viscosity, this drug combination should be avoided, if possible. Further evaluation of this combination needs to be made.
    Thalidomide: (Moderate) Thalidomide and epoetin alfa should be used cautiously due an increased risk of thromboembolism.

    PREGNANCY AND LACTATION

    Pregnancy

    Multidose vials of epoetin alfa are contraindicated during pregnancy due to the use of benzyl alcohol as a preservative. When epoetin alfa therapy is needed during pregnancy, use a single-dose vial, which is benzyl alcohol-free. Consider the benefits and risks of epoetin alfa single-dose vials for the mother and possible risks to the fetus when prescribing epoetin alfa to a pregnant woman. The limited available data on epoetin alfa use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. There are reports of intrauterine growth restriction and polyhydramnios in women with chronic renal disease, which is associated with an increased risk for these adverse pregnancy outcomes. In animal reproductive and developmental toxicity studies, embryofetal death, skeletal anomalies, and growth defects occurred when pregnant rats received epoetin alfa at doses approximating the clinical recommended starting doses.

    Multidose vials of epoetin alfa are contraindicated in breast-feeding due to the use of benzyl alcohol as a preservative. Advise breast-feeding women to not breast-feed for at least 2 weeks after the last dose of epoetin alfa, if a multidose vial was used. Do not mix epoetin alfa with bacteriostatic saline containing benzyl alcohol. Use caution when administering epoetin alfa from a single-dose vial to a breast-feeding woman. There is no information regarding the presence of epoetin alfa in human milk, the effects on the breast-fed infant, or the effects on milk production. Endogenous erythropoietin is present in human milk.

    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 3 times a week; however, a greater response is not seen at doses more than 300 units/kg 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. Whether the drug crosses the placenta or is distributed into breast milk has not been evaluated. 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 and drug transporters: none

    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.