EPOETIN ALFA 
■ EPOETIN ALFA-epbxa
Pronounciation
Trade Name(s)
Epoetin alfa-epbxais a biosimilar drug of epoetin alfa (Epogen, Procrit). Unless specifically stated otherwise, information in this monograph applies to all formulations of epoetin-alfa.
In all situations, rate of hematocrit increase is dose dependent and varies among patients. Availability of iron stores, baseline hematocrit, and concurrent medical problems affect the rate and extent of response. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding) before initiating epoetin alfa. Use the lowest dose for each patient that will gradually increase the hemoglobin concentration to avoid the need for RBC transfusion; see Precautions and Monitor.
Anemia associated with chronic kidney disease (CKD) for patients on dialysis:
Initiate epoetin when the hemoglobin level is less than 10 Gm/dL. Starting dose: 50 to 100 units/kg of body weight three times a week. May be given by IV or SC injection or into the venous line at the end of a dialysis session. The IV route is recommended in patients on hemodialysis; see Precautions.
Anemia associated with chronic kidney disease (CKD) for patients NOT on dialysis:
Consider initiating epoetin only when the hemoglobin level is less than 10 Gm/dL and the following two considerations apply: (1) the rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion, and (2) reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal. Starting dose: 50 to 100 units/kg of body weight three times a week.
Anemia in zidovudine-treated, HIV-infected patients:
May be given IV or SC. 100 units/kg 3 times a week. Obtain endogenous serum erythropoietin level (before transfusion) before initiating therapy; see Monitor. Serum erythropoietin levels in adults should be equal to or less than 500 mUnits/mL, and the zidovudine dose should be equal to or less than 4,200 mg/week.
Anemia associated with cancer patients on chemotherapy:
SC injection recommended. ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with certain types of cancer; see Precautions. Initiate epoetin in patients on cancer chemotherapy only if the hemoglobin is less than 10 Gm/dL and there is a minimum of 2 additional months of planned chemotherapy. Use the lowest dose necessary to avoid RBC transfusions. Starting dose: 150 units/kg of body weight 3 times a week until completion of chemotherapy course. An alternative schedule is 40,000 units weekly until completion of chemotherapy course.
Reduction of allogeneic blood transfusions in surgery patients:
SC injection recommended. Obtain hemoglobin before initiating therapy. Should be greater than 10 Gm/dL but less than or equal to 13 Gm/dL. 300 units/kg/day for 10 days before surgery, on the day of surgery, and for 4 days after surgery. An alternate regimen is 600 units/kg once each week on Days 21, 14, and 7 before surgery and again on the day of surgery. Deep venous thrombosis prophylaxis is recommended during epoetin therapy (e.g., enoxaparin [Lovenox]); see Precautions.
May be given by IV or SC injection. The IV route is recommended in patients on hemodialysis; see Precautions. Use the lowest dose for each patient that will gradually increase the hemoglobin concentration to avoid the need for RBC transfusion; see Precautions and Monitor.
Anemia of CKD in pediatric patients 1 month to 16 years of age:
Initiate epoetin when the hemoglobin level is less than 10 Gm/dL. Starting dose: 50 units/kg of body weight 3 times a week. May be given into the venous line at the end of the dialysis session.
Anemia in zidovudine-treated, HIV-infected pediatric patients 8 months to 17 years (unlabeled):
Doses of 50 to 400 units/kg 2 to 3 times a week have been reported. See all comments under the similar section in Usual Dose. Adjust dose to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion; see Dose Adjustments.
Anemia associated with pediatric cancer patients on chemotherapy, ages 5 to 18 years:
See comments under Usual Dose. Starting dose: 600 units/kg IV weekly until completion of chemotherapy course. Do not exceed 40,000 units.
Dose adjustment is based on hemoglobin. Adjust dose to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion.
All adult and pediatric patients with CKD:
When adjusting therapy, consider hemoglobin rate of rise, hemoglobin rate of decline, ESA responsiveness, and hemoglobin variability. A single hemoglobin excursion may not require a dose adjustment. Dose should be started slowly and adjusted for each patient to achieve and maintain the lowest hemoglobin level sufficient to avoid the need for RBC transfusion. Allow sufficient time before adjusting a dose; increased hemoglobin levels may not be observed for 2 to 6 weeks.
■ Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently.
■ If the hemoglobin rises rapidly (e.g., more than 1 Gm/dL in any 2-week period), reduce the dose by 25% or more as needed to reduce rapid responses.
■ For patients who do not respond adequately after 4 weeks of therapy (e.g., the hemoglobin has not increased by more than 1 Gm/dL), increase the dose by 25%.
■ 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. Discontinue epoetin if responsiveness does not improve.
Adult patients with CKD on dialysis:
If the hemoglobin level approaches or exceeds 11 Gm/dL, reduce or interrupt the dose of epoetin.
Adult patients with CKD NOT on dialysis:
If the hemoglobin level exceeds 10 Gm/dL, reduce or interrupt the dose of epoetin.
If the hemoglobin level approaches or exceeds 12 Gm/dL, reduce or interrupt the dose of epoetin.
Zidovudine-treated, HIV-infected patients and cancer patients on chemotherapy:
If hemoglobin does not increase after 8 weeks of therapy, increase dose by 50 to 100 units/kg. May increase dose at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or dose reaches 300 units/kg.
■ Withhold dose if the hemoglobin exceeds 12 Gm/dL. Restart dose at 25% below previous dose when hemoglobin falls to less than 11 Gm/dL.
■ Discontinue epoetin if increase in hemoglobin is not achieved at a dose of 300 units/kg for 8 weeks.
Cancer patients on chemotherapy:
Reduce dose by 25% when the hemoglobin reaches a level needed to avoid transfusion or increases more than 1 Gm/dL in any 2-week period. Withhold dose if the hemoglobin exceeds a level needed to avoid transfusion, and restart at 25% below the previous dose when the hemoglobin approaches a level at which transfusions may be required.
■ Increase adult dose to 300 units/kg three times a week or 60,000 units weekly if hemoglobin increases by less than 1 Gm/dL and remains below 10 Gm/dL after the initial 4 weeks of therapy. Increase pediatric dose to 900 units/kg weekly if hemoglobin increases by less than 1 Gm/dL and remains below 10 Gm/dL after the initial 4 weeks of therapy. Do not exceed a dose of 60,000 units.
■ Discontinue epoetin after 8 weeks if no response as measured by hemoglobin levels or by continued need for RBC transfusions.
Available as a clear, colorless solution in numerous concentrations from 2,000 units /mL to 40,000 units/mL; check dose on vial carefully. May be given undiluted as an IV injection. Do not dilute (see exception below). Do not shake during preparation; will render it biologically inactive. Single-dose vial contains no preservatives. Use only 1 dose per vial, then discard. Never re-enter a preservative-free vial. Epogen and Procrit are available in a multidose vial with preservative (benzyl alcohol); sterile technique imperative. Do not use vials that have been shaken or frozen. Epogen and Procrit single-dose preservative-free vials may be admixed in a syringe with bacteriostatic NS in a 1:1 ratio at the time of administration except when administered to pregnant or lactating women, neonates, or infants.
Store all vials in refrigerator at 2° to 8° C (36° to 46° F) in original carton to protect from light. Refrigerate multiple-dose vial after initial use. Discard multiple-dose vial 21 days after initial entry. Do not freeze or shake any vial of epoetin-alfa.
Specific information not available for all formulations.
Manufacturers state, “Do not dilute or administer in conjunction with other drug solutions.” One source indicates there may be protein loss from adsorption to PVC containers and tubing. Manufacturer suggests it may be mixed 1-to-1 with bacteriostatic NS in a syringe when prepared from a single-dose vial.
An amino acid glycoprotein manufactured by recombinant DNA technology. Has the same biologic effects as erythropoietin produced naturally by the kidneys. Stimulates bone marrow to produce RBCs, increasing the reticulocyte count within 10 days and the red cell count, hemoglobin, and hematocrit within 2 to 6 weeks. Normal iron stores are necessary because it steps up RBC production to a rate above what the body usually makes. New cells need iron, which is quickly depleted. Half-life is 4 to 13 hours. Continued therapy will maintain improved RBC levels and decrease need for transfusions.
Treatment of anemia associated with chronic kidney disease in adults and pediatric patients, including patients on dialysis and not on dialysis, to decrease the need for red blood cell (RBC) transfusion.
■ Treatment of anemias related to zidovudine (AZT, Retrovir) therapy in HIV-infected patients.
■ To reduce the need for allogeneic blood transfusions among patients with perioperative hemoglobin greater than 10 to less than or equal to 13 Gm/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery.
■ Treatment of chemotherapy-induced anemia in adult cancer patients who have nonmyeloid malignancies in which anemia is due to the effect of concomitant myelosuppressive chemotherapy and who, upon initiation of therapy, have a minimum of 2 additional months of planned chemotherapy.
Not indicated for use in patients receiving hormonal agents, therapeutic biologic products, or radiotherapy unless receiving concomitant myelosuppressive chemotherapy.
■ Not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure; see Precautions.
■ Not indicated for patients with cancer who are receiving myelosuppressive chemotherapy and in whom the anemia can be managed by transfusion.
■ Has not been shown to improve quality of life, fatigue, or patient well-being.
■ Not indicated in patients scheduled for surgery who are willing to donate autologous blood.
■ Not indicated in patients undergoing cardiac or vascular surgery.
■ Not indicated as a substitute for a RBC transfusion in patients who require immediate correction of anemia.
Anemia of prematurity.
Known hypersensitivity to epoetin alfa, uncontrolled hypertension, pure red cell aplasia (PRCA). Epoetin alfa from multidose vials containing benzyl alcohol is contraindicated in neonates, infants, pregnant women, and nursing mothers.
May be given IV or SC in patients not receiving dialysis. May be given to dialysis patients into the venous line at the end of the dialysis procedure to eliminate additional venous access.
■ Erythropoiesis-stimulating agents (ESAs) increase the risk of death, MI, stroke, congestive heart failure, and thrombosis of hemodialysis vascular access and other thromboembolic events.
■ In clinical trials of patients with CKD, patients experienced greater risks of these adverse events when ESAs were administered to target a hemoglobin of greater than 11 Gm/dL. No trial has identified a hemoglobin target level, an epoetin alfa dose, or a dosing strategy that does not increase these risks. Use the lowest epoetin alfa dose sufficient to reduce the need for RBC transfusions. Providers and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse reactions.
■ Use with caution in patients with coexistent cardiovascular disease and stroke. Patients with CKD who have an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients.
■ In clinical trials, ESAs increased the risk of death in patients undergoing CABG surgery and the risk of deep venous thrombosis in patients undergoing orthopedic procedures.
■ Increases in hemoglobin of greater than 1 Gm/dL during any 2-week period have been associated with an increased incidence of cardiac arrest, exacerbations of hypertension, congestive heart failure (CHF), vascular thrombosis/ischemia/infarction, acute MI, deep vein thrombosis (DVT), pulmonary embolus, and fluid overload/edema and may be associated with neurologic events (e.g., seizures, stroke). See Dose Adjustments.
■ For lack or loss of hemoglobin response to epoetin alfa, initiate a search for causative factors (e.g., bleeding, infection, inflammation, iron deficiency). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for pure red cell aplasia (PRCA). In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to epoetin alfa therapy.
■ Not intended for use in anemias caused by iron or folate deficiencies, hemolysis, or GI bleeding or for use in treating symptoms of anemia, including dizziness, fatigue, low energy, poor quality of life, or shortness of breath.
■ PRCA and severe anemia, with or without other cytopenias, in association with neutralizing antibodies to native erythropoietin have been observed. Most often reported in patients with CKD who are receiving epoetin alfa by SC injection. Any patient who develops a sudden loss of response to epoetin alfa accompanied by severe anemia and low reticulocyte count should be evaluated. Physicians may contact manufacturer (Amgen) for help with the evaluation of these patients.
■ Administration of erythropoiesis-stimulating agents (ESAs) to cancer patients shortened the overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of some patients with breast, cervical, head and neck, lymphoid, and non–small-cell lung malignancies; see prescribing information for specific studies. To minimize these risks, as well as the risks of serious cardiovascular and thromboembolic events, use the lowest dose needed to avoid a red blood cell transfusion. Use only to treat anemia due to concomitant myelosuppressive chemotherapy, and discontinue after completion of a chemotherapy course.
■ BP may increase during therapy with epoetin. Hypertensive encephalopathy and seizures have been observed.
■ Patients with uncontrolled hypertension should not be treated with epoetin until BP has been adequately controlled.
■ Epoetin increases the risk of seizures in patients with CKD. Use with caution in patients with a seizure disorder.
■ Serious hypersensitivity reactions, including anaphylaxis, have been reported.
■ Blistering and skin exfoliation reactions, including erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN), have been reported.
■ Epogen and Procrit contain albumin and carry a risk for transmission of viral diseases or Creutzfeldt-Jakob disease. However, donor screening and manufacturing processes make this risk extremely remote.
■ Retacrit contains 0.5 mg of phenylalanine in each 1-mL single-dose vial (all concentrations) and may be harmful to patients with phenylketonuria (PKU). Consider combined daily amount of phenylalanine from all sources before prescribing Retacrit.
Monitor hemoglobin weekly in patients who are initiating therapy. Continue until stable and the maintenance dose has been established, then monitor at least monthly.
■ Monitor hemoglobin weekly for at least 4 weeks following adjustment of therapy. Once stabilized, continue to monitor at least monthly.
■ A biologic product. Monitor for S/S of hypersensitivity reactions.
■ Monitor BP routinely; initiation or intensification of antihypertensive therapy and dietary restrictions may be necessary. If BP is difficult to control by pharmacologic or dietary measures, the dose of epoetin should be reduced or withheld.
■ Normal iron stores required to support epoetin-stimulated erythropoiesis. Transferrin saturation should be at least 20% and ferritin at least 100 ng/mL. Monitor before and during therapy. Supplemental iron is usually required to increase and maintain transferrin saturation. Administration of IV parenteral iron may be necessary in some patients.
■ Monitor for the presence of premonitory neurologic symptoms during initiation of therapy or when dose is adjusted. Seizures have been reported; see Precautions.
■ Monitor patients with pre-existing vascular disease carefully (especially those with CKD); increase in hematocrit may precipitate a cerebrovascular accident, transient ischemic attack, or myocardial infarction.
■ Dialysis patients may require additional anticoagulation with heparin to prevent clotting of artificial kidney or clotting of the vascular access (AV shunt) and to maintain efficiency of the dialysis procedure.
Risk of seizures, especially during first 90 days of therapy. Contact provider for new-onset seizures, premonitory symptoms, or a change in seizure frequency.
■ Additional instruction (e.g., equipment, techniques) will be required in patients who will self-administer (manufacturer supplies brochure).
■ Stress importance of compliance with diet, iron, and vitamin (e.g., folic acid, B12) supplementation and BP control. Close monitoring of BP and Hgb is imperative.
■ Promptly report S/S of hypersensitivity or skin reactions, pain or swelling in legs, SOB, increase in BP, dizziness, or loss of consciousness.
■ Increased risk of mortality, serious cardiovascular events, thromboembolic events, and tumor progression or recurrence.
■ Read Medication Guide carefully. All patients should discuss the risks of using an ESA with a health care professional.
May present risk to fetus; benefits must justify risk.
■ Some formulations contain benzyl alcohol. Serious and fatal reactions, including “gasping syndrome,” can occur in neonates and infants treated with drugs preserved in benzyl alcohol. There is a potential for similar risks to fetuses and infants exposed to benzyl alcohol in utero or in breast-fed milk, respectively; see Contraindications.
■ Use caution in nursing mothers.
■ Indicated in pediatric patients ages 1 month to 16 years of age for the treatment of anemia associated with CKD requiring dialysis. Use of epoetin alfa in pediatric patients with CKD not requiring dialysis is supported by efficacy in pediatric patients requiring dialysis.
■ Safety and effectiveness for use in infants under 1 month of age not established.
■ Indicated in pediatric cancer patients ages 5 to 18 years for the treatment of anemia due to myelosuppressive chemotherapy.
■ Has been used in zidovudine-treated and anemic pediatric patients ages 8 months to 17 years. Data limited.
■ Pharmacokinetics (absorption, distribution, metabolism, and excretion) in children and adolescents similar to adults.
■ Limited data available for use in neonates. Clearance may be increased compared to adults.
Response similar to that found in younger patients; however, elderly patients may have a greater sensitivity to its effects. Retacrit: Response unknown due to insufficient numbers in studies.
Generally well tolerated. Occur most frequently in patients with chronic renal failure. Increased hypertension is common, and hypertensive encephalopathy and seizures can occur. Clotted vascular access (AV shunt) and clotting of the artificial kidney may occur during dialysis. Allergic reactions have been reported. Other reported side effects are those common to the underlying disease and not necessarily attributable to epoetin and include arthralgias, asthenia, bone marrow fibrosis, bone pain, cerebrovascular accident or transient ischemic attack (CVA/TIA), chest pain, chills, cough, deep vein thrombosis, depression, diarrhea, dizziness, dysphagia, edema, fatigue, fever, headache, hyperglycemia, hyperkalemia, hypokalemia, injection site irritation or pain, insomnia, muscle spasm, myocardial infarction, nausea, polycythemia, pruritus, rash, respiratory congestion, shortness of breath, stomatitis, tachycardia, upper respiratory tract infection, vomiting, and weight decrease. PRCA and severe anemia, with or without other cytopenias, in association with neutralizing antibodies have been reported; see Precautions.
Notify physician of all side effects; most will be treated symptomatically. Excessive hypertension may require discontinuation of epoetin until BP is controlled or may respond to reduction in dose of epoetin or to an increase in antihypertensive therapy. Reduce dose of epoetin in patients with an increase in hemoglobin over 1 Gm/dL in any 2-week period. Consider phlebotomy in toxicity. If overdose or polycythemia does occur, monitor closely for cardiovascular events and hematologic abnormalities. When resuming therapy, monitor closely for evidence of rapid increases in hemoglobin concentration (greater than 1 Gm/dL within 14 days) and reduce dose as indicated. Additional heparin may be required during dialysis to prevent clotting. Permanently discontinue therapy in patients with antibody-mediated anemia or severe cutaneous reactions. Patients should not be switched to other erythropoietic proteins because antibodies may cross-react. Treat minor hypersensitivity reactions symptomatically. Discontinue drug and treat anaphylaxis as indicated; resuscitate as necessary.