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    Epoetin Alfa

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    May.03.2024

    Epoetin Alfa

    Indications/Dosage

    Labeled

    • anemia

    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.[30100][63174]
      • In patients undergoing cardiac or vascular surgery. However, guidelines suggest it is reasonable to use an erythropoietin stimulating agent with iron supplementation several days before cardiac surgery to increase red cell mass in patients who have preoperative anemia, refuse blood cell transfusion, or are deemed high-risk for postoperative anemia.[66828]
      • As a substitute for RBC transfusions in patients who require immediate correction of anemia.[30100][63174]
    • Use only single-dose (i.e., benzyl alcohol-free) vials in neonates and infants.[30100]

    Off-Label

    • anemia of prematurity
    • hypoxic-ischemic encephalopathy
    † Off-label indication

    For the treatment of anemia

    for anemia due to chronic kidney disease to decrease the need for red blood cell transfusion

    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.[30100] [63174]

    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.[30100] [63174]

    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.[30100] [63174]

    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

    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.[30100] [63174]

    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.[30100] [63174]

    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.[30100] [63174]

    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.[30100] [63174]

    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.[30100] [45862] [63174]

    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.[53081] [53111] [53126] [53128] [53132] 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.[53126] [53132] [53133] Oral iron 2 to 9 mg/kg/day was also administered in most studies.

    for anemia associated with myelodysplastic syndrome† (MDS)

    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).[42462]

    For the treatment of hypoxic-ischemic encephalopathy (HIE)†

    Subcutaneous and Intravenous dosage

    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.[53134] [53135] 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.[53134] 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.[53135]

    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, the cause of decreased or lack of response should be evaluated.[30100][63174]

    Maximum Dosage Limits

    • 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.

    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.

    † Off-label indication
    Revision Date: 05/03/2024, 05:08:50 AM

    References

    30100 - Epogen (epoetin alfa) package insert. Thousand Oaks, CA: Amgen Inc.; 2024 Apr.42462 - Afdhal NH, Dieterich DT, Pockros PJ, et al. Epoetin alfa maintains ribavirin dose in HCV-infected patients: A prospective, double-blind, randomized controlled study. Gastroenterology 2004;126:1302-1311.45862 - Procrit (epoetin alfa) package insert. Thousand Oaks, CA: Amgen, Inc.; 2024 Apr.53081 - Ohls RK, Veerman MW, Christensen RD. Pharmacokinetics and effectiveness of recombinant erythropoietin administered to preterm infants by continuous infusion in total parenteral nutrition solution. J Pediatr. 1996; 128: 518- 524.53111 - Shannon KM, Keith JF 3rd, Mentzer WE, et al. Recombinant human erythropoietin stimulates erythropoiesis and reduces erythrocyte transfusions in very low birth weight preterm infants. Pediatrics. 1995; 95: 1-8.53126 - Meyer MP, Meyer JH, Commerford A. Recombinant human erythropoietin in the treatment of the anemia of prematurity: results of a double-blind, placebo-controlled study. Pediatrics. 1994; 93: 918-923.53128 - Halperin DS, Wacker P, Lacourt G, et al. Effects of recombinant human erythropoietin in infants with the anemia of prematurity: a pilot study. J Pediatr. 1990; 116: 779-86.53132 - Maier RF, Obladen M, Kattner E, et al. High-versus low-dose erythropoietin in extremely low birth weight infants. J Pediatr. 1998: 132; 866-70.53133 - Garcia MG, Hutson AD, Christensen RD. Effect of recombinant erthropoietin on "late" transfusion in the neonatal intensive care unit: a meta-analysis. J Perinatol. 2002; 22: 108-111.53134 - Zhu C, Kang W, Xu F. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. 2009; 124: e218.53135 - Elmahdy H, El-Mashad AR, El-Bahrawy H, et al. Human recombinant erthropoietin in asphyxia neonatorum: pilot trial. Pediatrics. 2010; 125: e1135.63174 - Retacrit (epoetin alfa-epbx) package insert. Lake Forest, IL: Hospira, Inc.; 2023 Apr.66828 - Tibi P, McClure RS, Huang J, et al. STS/SCA/AmSECT/SABM update to the clinical practice guidelines on patient blood management. Ann Thorac Surg 2021;S0003-4975(21)00556-7.

    How Supplied

    Epoetin Alfa Solution for injection

    Epogen 2,000unit/mL Solution for Injection (55513-0126) (Amgen Inc) nullEpogen 2,000unit/mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Procrit 2,000unit/ml Solution for Injection (59676-0302) (Janssen Biotech, Inc.) nullProcrit 2,000unit/ml Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 2,000units/mL Solution for Injection (00069-1305) (Pfizer Injectables) null

    Epoetin Alfa Solution for injection

    Retacrit 2000units/mL Solution for Injection (59353-0002) (Vifor (International) Inc.) null

    Epoetin Alfa Solution for injection

    Epogen 3,000unit/mL Solution for Injection (55513-0267) (Amgen Inc) nullEpogen 3,000unit/mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Procrit 3,000unit/ml Solution for Injection (59676-0303) (Janssen Biotech, Inc.) nullProcrit 3,000unit/ml Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 3,000units/mL Solution for Injection (00069-1306) (Pfizer Injectables) null

    Epoetin Alfa Solution for injection

    Retacrit 3,000units/mL Solution for Injection (59353-0003) (Vifor (International) Inc.) null

    Epoetin Alfa Solution for injection

    Epogen 4,000unit/mL Solution for Injection (55513-0148) (Amgen Inc) nullEpogen 4,000unit/mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Procrit 4,000unit/ml Solution for Injection (59676-0304) (Janssen Biotech, Inc.) nullProcrit 4,000unit/ml Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 4,000units/mL Solution for Injection (00069-1307) (Pfizer Injectables) nullRetacrit 4,000units/mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 4000units/mL Solution for Injection (59353-0004) (Vifor (International) Inc.) null

    Epoetin Alfa Solution for injection

    Epogen 10,000unit/mL Solution for Injection (55513-0144) (Amgen Inc) nullEpogen 10,000unit/mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Epogen 20,000unit/2mL Solution for Injection (55513-0283) (Amgen Inc) nullEpogen 20,000unit/2mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Procrit 10,000unit/ml Solution for Injection (59676-0310) (Janssen Biotech, Inc.) nullProcrit 10,000unit/ml Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Procrit 10,000unit/ml Solution for Injection (59676-0312) (Janssen Biotech, Inc.) nullProcrit 10,000unit/ml Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 10,000units/mL Solution for Injection (00069-1308) (Pfizer Injectables) nullRetacrit 10,000units/mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 10,000units/mL Solution for Injection (59353-0010) (Vifor (International) Inc.) null

    Epoetin Alfa Solution for injection

    Retacrit 20,000units/2mL Solution for Injection (00069-1318) (Pfizer Injectables) nullRetacrit 20,000units/2mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 20,000units/2mL Solution for Injection (59353-0220) (Vifor (International) Inc.) null

    Epoetin Alfa Solution for injection

    Epogen 20,000unit/mL Solution for Injection (55513-0478) (Amgen Inc) nullEpogen 20,000unit/mL Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Procrit 20,000unit/ml Solution for Injection (59676-0320) (Janssen Biotech, Inc.) nullProcrit 20,000unit/ml Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 20,000units/mL Solution for Injection (00069-1311) (Pfizer Injectables) null

    Epoetin Alfa Solution for injection

    Retacrit 20,000units/mL Solution for Injection (59353-0120) (Vifor (International) Inc.) null

    Epoetin Alfa Solution for injection

    Epogen 40,000unit/ml Solution for Injection (55513-0823) (Amgen Inc) (off market)Epogen 40,000unit/ml Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Procrit 40,000unit/ml Solution for Injection (59676-0340) (Janssen Biotech, Inc.) nullProcrit 40,000unit/ml Solution for Injection package photo

    Epoetin Alfa Solution for injection

    Retacrit 40,000units/mL Solution for Injection (00069-1309) (Pfizer Injectables) nullRetacrit 40,000units/mL Solution for Injection package photo

    Description/Classification

    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. The composition and number of carbohydrate chains on epoetin alfa are comparable to those found on the native protein. Epoetin alfa is FDA-approved for the treatment of anemia due to chronic kidney disease, zidovudine therapy in HIV patients, and chemotherapy in patients with non-myeloid malignancies and to reduce the need for allogeneic blood transfusions in surgical 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. 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 red blood cell transfusions.[30100][63174]

    Classifications

    • Blood and Blood Forming Organs
      • Anti-anemic Agents
        • Erythropoietin Agents
    Revision Date: 05/03/2024, 05:08:50 AM

    References

    30100 - Epogen (epoetin alfa) package insert. Thousand Oaks, CA: Amgen Inc.; 2024 Apr.63174 - Retacrit (epoetin alfa-epbx) package insert. Lake Forest, IL: Hospira, Inc.; 2023 Apr.

    Administration Information

    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.[30100] [63174]

    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.[45862]

    Subcutaneous Administration

    • Inject subcutaneously taking care not to inject intradermally.[30100][63174]

    Clinical Pharmaceutics Information

    From Trissel's 2‚Ñ¢ Clinical Pharmaceutics Database

    Epoetin alfa

    pH Range
    pH 6.6 to 7.2 (single-dose). pH 5.8 to 6.4 (multiple-dose). pH for Retacrit is 7 to 7.5 (single-dose) and 5.6 to 6.6 (multiple-dose).
    ReferencesEpogen (epoetin alfa) package insert. Thousand Oaks, CA. Amgen Inc. 2024; Apr
    ReferencesProcrit (epoetin alfa) pacakage insert. Thousand Oaks, CA. Amgen, Inc. 2024; Apr
    ReferencesRetacrit (epoetin alfa-epbx) package insert. New York, NY. Pfizer Labs. 2023; Apr
    Osmolality/Osmolarity
    Epoetin alfa injections are isotonic.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    Stability
    Epoetin alfa vials should not be shaken to prevent foam formation and inactivation of the drug. Prolonged vigorous shaking may denature and inactivate this protein drug. A small amount of flocculated protein is not indicative of substantial inactivation, but if the vial contains particulates or is discolored the drug should not be used. Packaged in Syringes: Epoetin alfa (preservative-free) 2000 to 10,000 units/mL is reported to be stable for 2 weeks at room temperature or refrigerated packaged in plastic tuberculin syringes. However, the absence of a preservative results in a recommendation to use shortly after drawing the product into syringes. Corbo et al. reported that unpreserved single-use epoetin alfa 10,000 units/mL diluted with benzyl alcohol-preserved bacteriostatic sodium chloride 0.9% to 4000 units/mL was stable for 12 weeks at room temperature and under refrigeration and the benzyl alcohol concentration (0.54%) was sufficient to pass the USP Antimicrobial Preservatives Effectiveness Test. However, small dilutions with a higher epoetin alfa concentration of 5000 units/mL and having a lower benzyl alcohol concentration did not pass this test. Naughton et al. reported that epoetin alfa 20,000 units/ml packaged in 1-ml Medsaver plastic syringes exhibited no loss of biological activity in 6 weeks stored under refrigeration.
    ReferencesAnon. Manufacturer's information and labeling. (Package insert).
    ReferencesCohen V, Jellinek SP, Teperikidis L, et al. Room-temperature storage of medications labeled for refrigeration. Am J Health-Syst Pharm. 2007; 64
    ReferencesCorbo DC, Suddith RL, Sharma B, et al. Stability, potency, and preservative effectiveness of epoetin alfa after addition of a bacteriostatic diluent. Am J Hosp Pharm. 1992; 49
    ReferencesMcEvoy GK (ed). AHFS Drug Information (current edition). Bethesda, MD: American Society of Health-System Pharmacists.
    ReferencesNaughton CA, Duppong LM, Forbes KD, et al. Stability of multidose, preserved formulation epoetin alfa in syringes for three and six weeks. Am J Health-Syst Pharm. 2003; 60
    Light Exposure
    Exposure to light for less than 24 hours does not affect epoetin alfa stability.
    ReferencesMcEvoy GK (ed). AHFS Drug Information (current edition). Bethesda, MD: American Society of Health-System Pharmacists.
    Sorption Leaching
    Dilution of epoetin alfa runs the risk of unacceptable sorption to surfaces if insufficient protein content exists in the solution. Ohls and Christensen reported on epoetin alfa diluted to a concentration of 100 units/mL in dextrose 10% with added albumin human at concentrations of 0.1, 0.05, and 0.01%. The solutions were prepared in polypropylene containers, drawn into Becton Dickinson syringes, delivered through "standard" (presumably PVC) microbore tubing, a T-connector, and a Teflon neonatal intravenous catheter. The solutions containing 0.1% and 0.05% albumin human delivered about 96% of the epoetin alfa over 24 hours. However, for the samples with only 0.01% albumin human, less than half of the epoetin alfa was delivered.
    ReferencesOhls RK, Christensen RD. Stability of human recombinant epoetin alfa in commonly used neonatal intravenous solutions. Ann Pharmacother. 1996; 30
    Other Information
    Sodium Bisulfite: Maeda et al. reported that sodium bisulfite that is frequently used as an antioxidant stabilizer in many drug products may result in a decrease of epoetin alfa activity.
    ReferencesMaeda Y, Nakamata M, Senga K, et al. Compatibility of recombinant human erythropoietin injection. Byoin Yakugaku. 1992; 18
    Revision Date: 05/03/2024, 05:08:50 AMCopyright 2004-2024 by Lawrence A. Trissel. All Rights Reserved.

    References

    30100 - Epogen (epoetin alfa) package insert. Thousand Oaks, CA: Amgen Inc.; 2024 Apr.45862 - Procrit (epoetin alfa) package insert. Thousand Oaks, CA: Amgen, Inc.; 2024 Apr.63174 - Retacrit (epoetin alfa-epbx) package insert. Lake Forest, IL: Hospira, Inc.; 2023 Apr.

    Adverse Reactions

    Mild

    • arthralgia
    • chills
    • cough
    • dizziness
    • fever
    • headache
    • infection
    • injection site reaction
    • insomnia
    • myalgia
    • nausea
    • pruritus
    • rash
    • urticaria
    • vitamin B6 deficiency
    • vomiting
    • weight loss

    Moderate

    • anemia
    • antibody formation
    • bone pain
    • depression
    • dysphagia
    • edema
    • encephalopathy
    • erythema
    • hyperglycemia
    • hypertension
    • hypokalemia
    • leukopenia
    • phlebitis
    • stomatitis

    Severe

    • anaphylactoid reactions
    • angioedema
    • bronchospasm
    • erythema multiforme
    • heart failure
    • myocardial infarction
    • porphyria
    • pulmonary embolism
    • red cell aplasia
    • seizures
    • Stevens-Johnson syndrome
    • stroke
    • thromboembolism
    • thrombosis
    • toxic epidermal necrolysis

    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.[30100] [63174] 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.[30100]

    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 adult trials of 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.[30100] [45862] [63174]

    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.[27008] [27009] 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.[30100] [45862] [63174] 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.[27010] 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.[30100]

    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.[30100] [63174] 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.[32872] 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.[30100] [63174]

    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 persons living with HIV, 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. Due to the effects on erythropoiesis, abuse of epoetin alfa may be seen in athletes. Misuse of medications that increase erythropoiesis, such as epoetin alfa, by healthy persons may lead to life-threatening cardiovascular complications (e.g., stroke, myocardial infarction, and thromboembolism).[30100] [45862] 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 vs. 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).[30100] [33816] [63174]

    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.[30100] [45862] [63174]

    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.[30100] [45862] [63174]

    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.[30100] [45862] [63174]

    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.[30100] [45862] [63174]

    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.[30100] [45862] [63174]

    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.[30100] [45862] [63174]

    Porphyria has been reported with the postmarketing use of epoetin alfa.[30100] [45862] [63174]

    Epoetin increases hemoglobin synthesis decreasing erythrocyte pyridoxine status and may lead to vitamin B6 deficiency. Coadministration of low dose or moderate dose vitamin B6 may be beneficial. Supervise closely and monitor regularly, especially in patients with renal impairment.[63388]

    Revision Date: 05/03/2024, 05:08:50 AM

    References

    27008 - Casadevall N, Nataf J, Viron B, et al. Pure red cell aplasia and antierythropoietin antibodies in patients treated with recombinant erythropoietin. N Engl J Med 2002;346:469-475.27009 - Bunn HF. Drug-induced autoimmune red cell aplasia. N Engl J Med 2002;346:522-523.27010 - Gershon SK, Luksemburg H, Cote T, et al. Pure red cell aplasia and recombinant erythropoietin. N Engl J Med 2002;346:1584-1585.30100 - Epogen (epoetin alfa) package insert. Thousand Oaks, CA: Amgen Inc.; 2024 Apr.32872 - Singh AK, Szczech L, Tang KL, et al. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med 2006; 355:2085-98.33816 - Bennett CL, Silver SM, Djulbegovic B, et al. Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 2008;299:914-24.45862 - Procrit (epoetin alfa) package insert. Thousand Oaks, CA: Amgen, Inc.; 2024 Apr.63174 - Retacrit (epoetin alfa-epbx) package insert. Lake Forest, IL: Hospira, Inc.; 2023 Apr.63388 - Nutrient-Drug Interactions and Drug-Induced Nutrient Depletions. In: Stargrove MB, Treasure J, McKee DL. Herb, Nutrient, and Drug Interactions: Clinical Implications and Therapeutic Strategies. St. Louis: Mosby Elsevier; 2008:173-831.

    Contraindications/Precautions

    Absolute contraindications are italicized.

    • red cell aplasia
    • angina
    • anticoagulant therapy
    • benzyl alcohol hypersensitivity
    • bleeding
    • breast-feeding
    • cardiac disease
    • coronary artery bypass graft surgery (CABG)
    • dialysis
    • folate deficiency
    • heart failure
    • hematological disease
    • hemoglobin concentration greater than 11 g/dl
    • hemolytic anemia
    • hyperparathyroidism
    • hypertension
    • hypothyroidism
    • infants
    • infection
    • inflammation
    • iron-deficiency anemia
    • malnutrition
    • mortality
    • myelodysplastic syndrome (MDS)
    • myocardial infarction
    • neonates
    • neoplastic disease
    • phenylketonuria
    • pregnancy
    • renal failure
    • renal impairment
    • seizure disorder
    • seizures
    • sickle cell disease
    • stroke
    • surgery
    • thalassemia
    • thromboembolism
    • viral infection
    • vitamin B12 deficiency

    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.[30100][45862][63174]

    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.[30100] [63174]

    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.[30100] [63174]

    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.[30100] [45862] [63174]

    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.[30100] [63174]

    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.[30100] [63174] However, guidelines suggest it is reasonable to use ESAs with iron supplementation several days before cardiac surgery to increase red cell mass in patients who have preoperative anemia, refuse blood cell transfusion, or are deemed high-risk for postoperative anemia; studies have reported no adverse effects associated with short-term ESA pretreatment.[66828] 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.[30100] [63174]

    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.[30100] [63174]

    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.[30100] [63174] [66652] 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.[66652]

    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.[30100] [63174]

    Certain formulations of epoetin alfa contain albumin. As with other products derived from or purified with human blood components, the remote possibility of contamination with Creutzfeldt-Jakob disease (CJD) or other viral infections exists in patients receiving albumin. The manufacturing processes are designed to reduce the risk of transmitting viral infection. No cases of transmission of viral illness or CJD have ever been identified for albumin.[30100] [45862]

    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.[63174]

    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.[30100] [63174]

    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.[30100] [63174]

    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.[30100] [63174]

    Revision Date: 05/03/2024, 05:08:50 AM

    References

    30100 - Epogen (epoetin alfa) package insert. Thousand Oaks, CA: Amgen Inc.; 2024 Apr.45862 - Procrit (epoetin alfa) package insert. Thousand Oaks, CA: Amgen, Inc.; 2024 Apr.63174 - Retacrit (epoetin alfa-epbx) package insert. Lake Forest, IL: Hospira, Inc.; 2023 Apr.66652 - Kidney Disease: Improving Global Outcomes (KDIGO) Anemia Work Group. KDIGO Clinical Practice Guideline for Anemia in Chronic Kidney Disease. Kidney Int Suppl. 2012;2:279-335.66828 - Tibi P, McClure RS, Huang J, et al. STS/SCA/AmSECT/SABM update to the clinical practice guidelines on patient blood management. Ann Thorac Surg 2021;S0003-4975(21)00556-7.

    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.[23683]

     

    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.[30100]

    Revision Date: 05/03/2024, 05:08:50 AM

    References

    23683 - Erslev AJ. Erythropoietin. Leukemia Res 1990;14:683-8.30100 - Epogen (epoetin alfa) package insert. Thousand Oaks, CA: Amgen Inc.; 2024 Apr.

    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.[30100]

     

    Affected cytochrome P450 isoenzymes and drug transporters: 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.[30100]

    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.[30100][63174]

    Special Populations

    Renal Impairment

    Epoetin alfa half-life in patients with chronic renal failure after IV administration is 4 to 13 hours. The drug is not removed by hemodialysis.[30100][63174]

    Pediatrics

    Children and Adolescents

    The pharmacokinetic profile of epoetin alfa in children and adolescents appears to be similar to that of adults.[30100][63174]

     

    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.[30100][63174] 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).[53081]

     

    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.[53082]

    Revision Date: 05/03/2024, 05:08:50 AM

    References

    30100 - Epogen (epoetin alfa) package insert. Thousand Oaks, CA: Amgen Inc.; 2024 Apr.53081 - Ohls RK, Veerman MW, Christensen RD. Pharmacokinetics and effectiveness of recombinant erythropoietin administered to preterm infants by continuous infusion in total parenteral nutrition solution. J Pediatr. 1996; 128: 518- 524.53082 - Juul SE, McPherson RJ, Bauer LA, Ledbetter KJ, et al. A phase I/II trial of high-dose erythropoietin in extremely low birth weight infants: pharmacokinetics and safety. Pediatrics. 2008; 122: 383.63174 - Retacrit (epoetin alfa-epbx) package insert. Lake Forest, IL: Hospira, Inc.; 2023 Apr.

    Pregnancy/Breast-feeding

    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.[30100] [63174]

    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.[30100] [63174]

    Revision Date: 05/03/2024, 05:08:50 AM

    References

    30100 - Epogen (epoetin alfa) package insert. Thousand Oaks, CA: Amgen Inc.; 2024 Apr.45862 - Procrit (epoetin alfa) package insert. Thousand Oaks, CA: Amgen, Inc.; 2024 Apr.63174 - Retacrit (epoetin alfa-epbx) package insert. Lake Forest, IL: Hospira, Inc.; 2023 Apr.

    Interactions

    Level 3 (Moderate)

    • Lenalidomide
    • Thalidomide
    Lenalidomide: (Moderate) Monitor for signs and symptoms of thromboembolic events if concomitant use of lenalidomide and an erythropoiesis-stimulating agent (ESA) is required. Both medications have been associated with venous thromboembolism and concomitant use may increase the risk of thrombosis. [49713] [58806] Thalidomide: (Moderate) Monitor for signs and symptoms of thromboembolic events if concomitant use of thalidomide and an erythropoiesis-stimulating agent (ESA) is required. Both medications have been associated with venous thromboembolism and concomitant use may increase the risk of thrombosis. [49713] [58806]
    Revision Date: 05/03/2024, 05:08:50 AM

    References

    49713 - Thalomid (thalidomide) package insert. Summit, NJ: Celgene Corporation; 2013 Feb.58806 - Revlimid (lenalidomide) tablets package insert. Summit, NJ: Celgene Corporation; 2023 March.

    Monitoring Parameters

    • CBC
    • ferritin
    • hemoglobin/hematocrit
    • serum electrolytes
    • serum iron
    • serum uric acid
    • transferrin

    US Drug Names

    • Epogen
    • Procrit
    • Retacrit
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