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Epoetin Alfa

Pronunciation

Pronunciation

(e POE e tin AL fa)

Index Terms

  • rHuEPO
  • rHuEPO-α
  • EPO
  • Epoetin Alfa, Recombinant
  • Erythropoiesis-Stimulating Agent (ESA)
  • Erythropoietin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Injection:

Epogen: 10,000 units/mL (2 mL); 20,000 units/mL (1 mL) [contains benzyl alcohol]

Procrit: 10,000 units/mL (2 mL); 20,000 units/mL (1 mL) [contains benzyl alcohol]

Solution, Injection [preservative free]:

Epogen: 2000 units/mL (1 mL); 3000 units/mL (1 mL); 4000 units/mL (1 mL); 10,000 units/mL (1 mL)

Procrit: 2000 units/mL (1 mL); 3000 units/mL (1 mL); 4000 units/mL (1 mL); 10,000 units/mL (1 mL); 40,000 units/mL (1 mL)

Brand Names: U.S.

  • Epogen
  • Procrit

Pharmacologic Category

  • Colony Stimulating Factor
  • Erythropoiesis-Stimulating Agent (ESA)
  • Hematopoietic Agent

Pharmacology

Induces erythropoiesis by stimulating the division and differentiation of committed erythroid progenitor cells; induces the release of reticulocytes from the bone marrow into the bloodstream, where they mature to erythrocytes. There is a dose response relationship with this effect. This results in an increase in reticulocyte counts followed by a rise in hematocrit and hemoglobin levels.

Absorption

SubQ: Slow (McMahon 1990; Salmonson 1990)

Distribution

Vd: 9 L; rapid in the plasma compartment; concentrated in liver, kidneys, and bone marrow; similar to extracelluar plasma volume in adults (McMahon 1990; Salmonson1990); reported to be higher in premature neonates on body weight basis (Brown 1993)

Metabolism

Some degradation does occur

Excretion

Feces (majority); urine (small amounts, 10% unchanged in normal volunteers)

Onset of Action

Several days; Peak effect: Hemoglobin level: 2 to 6 weeks

Time to Peak

Serum: Pediatric patients >1 month and Adults: Chronic kidney disease: SubQ: 5 to 24 hours

Half-Life Elimination

Neonates: With high doses, nonlinear kinetics have been observed (Wu, 2012)

Anemia of prematurity:

PMA <32 week (weight: 800 ± 206 grams): IV: 8.1 ± 2.7 hours; SubQ: 7.1 ± 4.1 hours (Brown 1993)

PMA ≥32 weeks (weight range: 1330 to 1740 g): SubQ: Median: 7.9 hours (range: 5.6 to 19.4 hours) (Krishnan 1996)

Neuroprotective/hypoxic ischemia encephalopathy (HIE) (Wu, 2012): ≥36 weeks GA; IV:

250 units/kg: 7.6 ± 6.9 hours

500 units/kg: 7.2 ± 1.9 hours

1,000 units/kg: 15 ± 4.5 hours

2,500 units/kg: 18.7 ± 4.7 hours

Infants, Children, and Adolescents: Chronic kidney disease: IV: 4 to 13 hours

Adults: Cancer: SubQ: 16 to 67 hours; Chronic kidney disease: IV: 4 to 13 hours

Use: Labeled Indications

Anemia: Treatment of anemia due to concurrent myelosuppressive chemotherapy in patients with cancer (nonmyeloid malignancies) receiving chemotherapy (palliative intent) for a planned minimum of 2 additional months of chemotherapy; treatment of anemia due to chronic kidney disease (including patients on dialysis and not on dialysis) to decrease the need for RBC transfusion; treatment of anemia associated with HIV (zidovudine) therapy when endogenous erythropoietin levels ≤500 mUnits/mL; reduction of allogeneic RBC transfusion for elective, noncardiac, nonvascular surgery when perioperative hemoglobin is >10 to ≤13 g/dL and there is a high risk for blood loss

Limitations of use: Epoetin alfa has not been shown to improve quality of life, fatigue, or patient well-being. Epoetin alfa is not indicated for use under the following conditions:

- Cancer patients receiving hormonal therapy, therapeutic biologic products, or radiation therapy unless also receiving concurrent myelosuppressive chemotherapy

- Cancer patients receiving myelosuppressive chemotherapy when the expected outcome is curative

- Surgery patients who are willing to donate autologous blood

- Surgery patients undergoing cardiac or vascular surgery

- As a substitute for RBC transfusion in patients requiring immediate correction of anemia

Use: Unlabeled

Treatment of symptomatic anemia in myelodysplastic syndrome (MDS)

Contraindications

Serious allergic reactions to epoetin alfa or any component of the formulation; uncontrolled hypertension; pure red cell aplasia (PRCA) that begins after treatment with epoetin alfa or other epoetin protein drugs; multidose vials contain benzyl alcohol and are contraindicated in neonates, infants, pregnant women, and nursing women

Dosing: Adult

Note: Evaluate iron status in all patients before and during treatment and maintain iron repletion.

Anemia associated with chronic kidney disease (CKD): Individualize dosing and use the lowest dose necessary to reduce the need for RBC transfusions.

Chronic kidney disease patients ON dialysis (IV route is preferred for hemodialysis patients; initiate treatment when hemoglobin is <10 g/dL; reduce dose or interrupt treatment if hemoglobin approaches or exceeds 11 g/dL): IV, SubQ: Initial dose: 50 to 100 units/kg 3 times a week

Chronic kidney disease patients NOT on dialysis (consider initiating treatment when hemoglobin is <10 g/dL; use only if rate of hemoglobin decline would likely result in RBC transfusion and desire is to reduce risk of alloimmunization and/or other RBC transfusion-related risks; reduce dose or interrupt treatment if hemoglobin exceeds 10 g/dL): IV, SubQ: Initial dose: 50 to 100 units/kg 3 times a week

Dosage adjustments for chronic kidney disease patients (either on dialysis or not on dialysis): Do not increase dose more frequently than every 4 weeks (dose decreases may occur more frequently); avoid frequent dosage adjustments.

If hemoglobin does not increase by >1 g/dL after 4 weeks: Increase dose by 25%

If hemoglobin increases >1 g/dL in any 2-week period: Reduce dose by ≥25%

Inadequate or lack of response over a 12-week escalation period: Further increases are unlikely to improve response and may increase risks; use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid RBC transfusions and evaluate patient for other causes of anemia. Discontinue therapy if responsiveness does not improve.

Anemia due to chemotherapy in cancer patients: Initiate treatment only if hemoglobin <10 g/dL and anticipated duration of myelosuppressive chemotherapy is at least 2 additional months. Titrate dosage to use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions. Discontinue erythropoietin following completion of chemotherapy. SubQ: Initial dose: 150 units/kg 3 times a week or 40,000 units once weekly until completion of chemotherapy

Dosage adjustments:

If hemoglobin does not increase by ≥1 g/dL and remains below 10 g/dL after initial 4 weeks: Increase to 300 units/kg 3 times a week or 60,000 units weekly; discontinue after 8 weeks of treatment if RBC transfusions are still required or there is no hemoglobin response

If hemoglobin exceeds a level needed to avoid red blood cell transfusion: Withhold dose; resume treatment with a 25% dose reduction when hemoglobin approaches a level where transfusions may be required.

If hemoglobin increases >1 g/dL in any 2-week period or hemoglobin reaches a level sufficient to avoid red blood cell transfusion: Reduce dose by 25%.

Anemia due to zidovudine in HIV-infected patients: Titrate dosage to use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions. Hemoglobin levels should not exceed 12 g/dL.

Serum erythropoietin levels ≤500 mUnits/mL and zidovudine doses ≤4200 mg/week): IV, SubQ: Initial: 100 units/kg 3 times a week; if hemoglobin does not increase after 8 weeks, increase dose by ~50 to 100 units/kg at 4 to 8 week intervals until hemoglobin reaches a level sufficient to avoid RBC transfusion; maximum dose: 300 units/kg. Withhold dose if hemoglobin exceeds 12 g/dL, may resume treatment with a 25% dose reduction once hemoglobin <11 g/dL. Discontinue if hemoglobin increase is not achieved with 300 units/kg for 8 weeks.

Surgery patients (perioperative hemoglobin should be >10 g/dL and ≤13 g/dL; DVT prophylactic anticoagulation is recommended): SubQ: Initial dose:

300 units/kg/day for 15 days total, beginning 10 days before surgery, on the day of surgery, and for 4 days after surgery or

600 units/kg once weekly for 4 doses, given 21-, 14-, and 7 days before surgery, and on the day of surgery

Symptomatic anemia associated with myelodysplastic syndrome (off-label use): SubQ: 150 to 300 units/kg once daily (Greenburg 2009) or 450 to 1000 units/kg/week in divided doses, 3 to 7 times a week (Hellström-Lindberg 1995) or 60,000 units once weekly (Park 2008)

Dosing: Geriatric

Refer to adult dosing.

Dosing: Pediatric

Note: Evaluate iron status in all patients before and during treatment and maintain iron repletion.

Anemia associated with chronic kidney disease (CKD): Individualize dosing and use the lowest dose necessary to reduce the need for RBC transfusions.

Chronic kidney disease patients ON dialysis (IV route is preferred for hemodialysis patients; initiate treatment when hemoglobin is <10 g/dL; reduce dose or interrupt treatment if hemoglobin approaches or exceeds 11 g/dL):

Pediatrics 1 month to 16 years: IV, SubQ: Initial dose: 50 units/kg 3 times a week

Dosage adjustments for chronic kidney disease patients: Do not increase dose more frequently than every 4 weeks (dose decreases may occur more frequently); avoid frequent dosage adjustments

If hemoglobin does not increase by >1 g/dL after 4 weeks: Increase dose by 25%

If hemoglobin increases >1 g/dL in any 2-week period: Reduce dose by ≥25%

Inadequate or lack of response over a 12-week escalation period: Further increases are unlikely to improve response and may increase risks; use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid RBC transfusions and evaluate patient for other causes of anemia. Discontinue therapy if responsiveness does not improve.

Anemia due to chemotherapy in cancer patients: Initiate treatment only if hemoglobin <10 g/dL and anticipated duration of myelosuppressive chemotherapy is at least 2 additional months. Titrate dosage to use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions. Discontinue erythropoietin following completion of chemotherapy.

Children ≥5 years and Adolescents: IV: Initial dose: 600 units/kg once weekly until completion of chemotherapy.

Dosage adjustments:

If hemoglobin does not increase by ≥1 g/dL and remains <10 g/dL after initial 4 weeks: Increase to 900 units/kg (maximum dose: 60,000 units); discontinue after 8 weeks of treatment if RBC transfusions are still required or there is no hemoglobin response.

If hemoglobin exceeds a level needed to avoid red blood cell transfusion: Withhold dose; resume treatment with a 25% dose reduction when hemoglobin approaches a level where transfusions may be required.

If hemoglobin increases >1 g/dL in any 2-week period or hemoglobin reaches a level sufficient to avoid red blood cell transfusion: Reduce dose by 25%.

Anemia due to zidovudine in HIV-infected patients: Titrate dosage to use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions. Hemoglobin levels should not exceed 12 g/dL. Children 8 months to 17 years (based on limited data): IV, SubQ: Reported dosing range: 50 to 400 units/kg 2 to 3 times a week

Dosing: Renal Impairment

No dosage adjustment necessary.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer's labeling.

Reconstitution

Prior to SubQ administration, preservative free solutions may be mixed with bacteriostatic NS containing benzyl alcohol 0.9% in a 1:1 ratio.

Administration

Do not shake.

SubQ is the preferred route of administration except in patients with CKD on hemodialysis.; usually administered undiluted, although may use a 1:1 dilution with bacteriostatic NS.

Patients with CKD on hemodialysis: IV route preferred; it may be administered into the venous line at the end of the dialysis procedure

Compatibility

Stable in D10W with albumin 0.05%, D10W with albumin 0.1%; incompatible with D10W with albumin 0.01%, D10W, NS.

Storage

Vials should be stored at 2°C to 8°C (36°F to 46°F); Do not freeze. Do not shake. Protect from light.

Single-dose 1 mL vial contains no preservative: Use one dose per vial. Do not re-enter vial; discard unused portions.

Single-dose vials (except 40,000 units/mL vial) are stable for 2 weeks at room temperature (Cohen 2007). Single-dose 40,000 units/mL vial is stable for 1 week at room temperature.

Multidose 1 mL or 2 mL vial contains preservative. Store at 2°C to 8°C after initial entry and between doses. Discard 21 days after initial entry.

Multidose vials (with preservative) are stable for 1 week at room temperature (Cohen 2007).

Prefilled syringes containing the 20,000 units/mL formulation with preservative are stable for 6 weeks refrigerated (2°C to 8°C) (Naughton 2003).

Dilutions of 1:10 and 1:20 (1 part epoetin alfa:19 parts sodium chloride) are stable for 18 hours at room temperature (Ohls 1996).

Prior to SubQ administration, preservative free solutions may be mixed with bacteriostatic NS containing benzyl alcohol 0.9% in a 1:1 ratio (Corbo 1992).

Dilutions of 1:10 in D10W with human albumin 0.05% or 0.1% are stable for 24 hours.

Drug Interactions

Lenalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Lenalidomide. Monitor therapy

Nandrolone: May enhance the stimulatory effect of Erythropoiesis-Stimulating Agents. Specifically, nandrolone may enhance the erythropoiesis stimulatory effect of Erythropoiesis-Stimulating Agents. Monitor therapy

Pomalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Pomalidomide. Monitor therapy

Thalidomide: Erythropoiesis-Stimulating Agents may enhance the thrombogenic effect of Thalidomide. Monitor therapy

Adverse Reactions

>10%:

Cardiovascular: Hypertension (3% to 28%)

Central nervous system: Headache (5% to 18%)

Dermatologic: Pruritus (12% to 21%), skin rash (2% to 19%)

Gastrointestinal: Nausea (35% to 56%), vomiting (12% to 28%)

Local: Injection site reaction (7% to 13%)

Neuromuscular & skeletal: Arthralgia (10% to 16%)

Respiratory: Cough (4% to 26%)

Miscellaneous: Fever (10% to 42%)

1% to 10%:

Cardiovascular: Deep vein thrombosis, edema, pulmonary embolism, thrombosis

Central nervous system: Chills, depression, dizziness, insomnia

Dermatologic: Urticaria

Endocrine & metabolic: Hyperglycemia, hypokalemia, weight loss

Gastrointestinal: Dysphagia, stomatitis

Hematologic & oncologic: Leukopenia

Neuromuscular & skeletal: Muscle spasm, myalgia, ostealgia

Respiratory: Respiratory congestion, upper respiratory tract infection

Miscellaneous: Vascular access complications (clotting)

<1% (Limited to important or life-threatening): Anaphylaxis, angioedema, antibody development (neutralizing), bronchospasm, cerebrovascular accident, erythema, hypersensitivity reaction, hypertensive encephalopathy, myocardial infarction, porphyria, pure red cell aplasia, retinal thrombosis (arterial), seizure, tachycardia, temporal thrombosis, thrombophlebitis, thrombosis (microvascular), transient ischemic attacks, tumor growth, venous thrombosis

ALERT: U.S. Boxed Warning

Cardiovascular events:

Erythropoiesis-stimulating agents (ESAs) increase the risk of death, myocardial infarction (MI), stroke, venous thromboembolism, thrombosis of vascular access.

Chronic kidney disease:

In controlled trials, patients experienced greater risks of death, serious adverse cardiovascular reactions, and stroke when administered ESAs to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Use the lowest epoetin alfa dose sufficient to reduce the need for red blood cell (RBC) transfusions.

Cancer:

ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in some clinical studies in patients with breast, non–small cell lung, head and neck, lymphoid, and cervical cancers. Because of these risks, health care providers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense epoetin alfa to patients with cancer. To enroll in the ESA APPRISE Oncology Program, visit http://www.esa-apprise.com or call 1-866-284-8089 for further assistance. To decrease these risks, as well as the risk of serious cardiovascular and thrombovascular events, use the lowest dose needed to avoid RBC transfusions. Use ESAs only for treatment of anemia from concomitant myelosuppressive chemotherapy. ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is cure. Discontinue following the completion of a chemotherapy course.

Perisurgery:

Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended.

Warnings/Precautions

Concerns related to adverse effects:

• Cardiovascular events: [US Boxed Warning]: Erythropoiesis-stimulating agents (ESAs) increased the risk of serious cardiovascular events, myocardial infarction, stroke, venous thromboembolism, vascular access thrombosis, and mortality in clinical studies when administered to target hemoglobin levels >11 g/dL (and provide no additional benefit); a rapid rise in hemoglobin (>1 g/dL over 2 weeks) may also contribute to these risks.

• Hypersensitivity: Potentially serious allergic reactions have been reported (rarely), including anaphylactic reactions, angioedema, bronchospasm, rash, and urticaria. Discontinue immediately (and permanently) in patients who experience serious allergic/anaphylactic reactions.

• Pure red cell aplasia (PRCA): Cases of severe anemia and PRCA have been reported, predominantly in patients with chronic kidney disease receiving SubQ epoetin alfa (the IV route is preferred for hemodialysis patients); cases have also been reported in patients with hepatitis C who were receiving ESAs, interferon, and ribavirin. Patients with a sudden loss of response (with severe anemia and a low reticulocyte count) should be evaluated for PRCA with associated neutralizing antibodies to erythropoietin; discontinue treatment (permanently) in patients with PRCA secondary to neutralizing antibodies to erythropoietin. Antibodies may cross-react; do not switch to another ESA in patients who develop antibody-mediated anemia.

Disease-related concerns:

• Cancer patients: [US Boxed Warning]: A shortened overall survival and/or increased risk of tumor progression or recurrence has been reported in studies with breast, cervical, head and neck, lymphoid, and non-small cell lung cancer patients. It is of note that in these studies, patients received ESAs to a target hemoglobin of ≥12 g/dL; although risk has not been excluded when dosed to achieve a target hemoglobin of <12 g/dL. [US Boxed Warnings]: To decrease these risks, and risk of cardio and thrombovascular events, use the lowest dose needed to avoid red blood cell transfusions. Use ESAs in cancer patients only for the treatment of anemia related to concurrent myelosuppressive chemotherapy; discontinue ESA following completion of the chemotherapy course. ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is curative. A dosage modification is appropriate if hemoglobin levels rise >1 g/dL per 2-week time period during treatment (Rizzo 2010). Use of ESAs has been associated with an increased risk of venous thromboembolism (VTE) without a reduction in transfusions in patients >65 years of age with cancer (Hershman 2009). Improved anemia symptoms, quality of life, fatigue, or well-being have not been demonstrated in controlled clinical trials.

• Chronic kidney disease patients: [US Boxed Warning]: An increased risk of death, serious cardiovascular events, and stroke was reported in chronic kidney disease (CKD) patients administered ESAs to target hemoglobin levels ≥11 g/dL; use the lowest dose sufficient to reduce the need for RBC transfusions. An optimal target hemoglobin level, dose or dosing strategy to reduce these risks has not been identified in clinical trials. Hemoglobin rising >1 g/dL in a 2-week period may contribute to the risk (dosage reduction recommended). CKD patients who exhibit an inadequate hemoglobin response to ESA therapy may be at a higher risk for cardiovascular events and mortality compared to other patients. ESA therapy may reduce dialysis efficacy (due to increase in red blood cells and decrease in plasma volume); adjustments in dialysis parameters may be needed. Patients treated with epoetin alfa may require increased heparinization during dialysis to prevent clotting of the extracorporeal circuit.

• Hypertension: Use with caution in patients with a history of hypertension (contraindicated in uncontrolled hypertension). An excessive rate of rise of hemoglobin is associated with hypertension or exacerbation of hypertension; decrease the epoetin alfa dose if the hemoglobin increase exceeds 1 g/dL in any 2-week period. Blood pressure should be controlled prior to start of therapy and monitored closely throughout treatment. Hypertensive encephalopathy has been reported with patients receiving erythropoietic therapy; monitor closely and control blood pressure.

• Perisurgery patients: [US Boxed Warning]: DVT prophylaxis is recommended in perisurgery patients due to the increased risk of DVT. Increased mortality was also observed in patients undergoing coronary artery bypass surgery who received epoetin alfa; these deaths were associated with thrombotic events. Epoetin alfa is not approved for reduction of red blood cell transfusion in patients undergoing cardiac or vascular surgery and is not indicated for surgical patients willing to donate autologous blood.

• Seizures: The risk for seizures is increased with epoetin alfa use in patients with chronic kidney disease; use with caution in patients with a history of seizures. Monitor closely for neurologic symptoms during the first several months of therapy.

• Severe anemia or acute blood loss: Due to the delayed onset of erythropoiesis, epoetin alfa is not recommended for acute correction of severe anemia or as a substitute for emergency transfusion.

Dosage form specific issues:

• Albumin: Product may contain albumin, which confers a theoretical risk of transmission of viral disease or Creutzfeldt-Jakob disease.

• Benzyl alcohol and derivatives: Some dosage forms may contain benzyl alcohol; large amounts of benzyl alcohol (≥99 mg/kg/day) have been associated with a potentially fatal toxicity (“gasping syndrome”) in neonates; the “gasping syndrome” consists of metabolic acidosis, respiratory distress, gasping respirations, CNS dysfunction (including convulsions, intracranial hemorrhage), hypotension and cardiovascular collapse (AAP ["Inactive" 1997]; CDC 1982); some data suggests that benzoate displaces bilirubin from protein binding sites (Ahlfors 2001); avoid or use dosage forms containing benzyl alcohol with caution in neonates. See manufacturer’s labeling.

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson 2002; Lucente 2000; Shelley 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade 1986; CDC 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Appropriate use:

- Oncology: The American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) 2010 updates to the clinical practice guidelines for the use of ESAs in patients with cancer indicate that ESAs are appropriate when used according to the parameters identified within the Food and Drug Administration (FDA) approved labeling for epoetin and darbepoetin afla (Rizzo 2010). ESAs are an option for chemotherapy associated anemia when the hemoglobin has fallen to <10 g/dL to decrease the need for RBC transfusions. ESAs should only be used in conjunction with concurrent chemotherapy. Although the FDA label now limits ESA use to the palliative setting, the ASCO/ASH guidelines suggest using clinical judgment in weighing risks versus benefits as formal outcomes studies of ESA use defined by intent of chemotherapy treatment have not been conducted.

- Cardiovascular disease: The American College of Physicians recommends against the use of ESAs in patients with mild to moderate anemia and heart failure or coronary heart disease (ACP [Qaseem 2013]). The ACCF/AHA 2013 Heart Failure Guidelines do not provide a clear recommendation on the use of ESAs in anemic heart failure patients. The effects of ESAs on quality of life measures, morbidity, and mortality are potentially modest and still unclear. Additionally, the safety of epoetin alfa has not been well studied in this population. The authors declined to provide an official recommendation regarding the use of ESAs pending the completion of ongoing randomized trials (ACCF/AHA [Yancy 2013]).

• Factors impairing erythropoiesis: Prior to treatment, correct or exclude deficiencies of iron, vitamin B12, and/or folate, as well as other factors which may impair erythropoiesis (inflammatory conditions, infections, bleeding). Poor response to therapy should prompt evaluation of potential factors impairing erythropoiesis, as well as possible malignant processes and hematologic disease (thalassemia, refractory anemia, myelodysplastic disorder), occult blood loss, hemolysis, ostetis fibrosa cystic, and/or bone marrow fibrosis.

• Iron supplementation: Prior to and periodically during therapy, iron stores must be evaluated. Supplemental iron is recommended if serum ferritin <100 mcg/L or serum transferrin saturation <20%. Most patients with chronic kidney disease will require iron supplementation.

• REMS program: [US Boxed Warning]: Because of the risks of decreased survival and increased risk of tumor growth or progression, health care providers and hospitals must enroll and comply with the ESA APPRISE Oncology Program to prescribe or dispense ESAs to cancer patients. Prescribers and patients will have to provide written documentation of discussed risks prior to each new course.

Monitoring Parameters

Transferrin saturation and serum ferritin (prior to and during treatment); hemoglobin (weekly after initiation and following dose adjustments until stable and sufficient to minimize need for RBC transfusion, CKD patients should be also be monitored at least monthly following hemoglobin stability); blood pressure; seizures (CKD patients following initiation for first few months, includes new-onset or change in seizure frequency or premonitory symptoms)

Cancer patients: Examinations recommended by the ASCO/ASH guidelines (Rizzo 2010) prior to treatment include: peripheral blood smear (in some situations a bone marrow exam may be necessary), assessment for iron, folate, or vitamin B12 deficiency, reticulocyte count, renal function status, and occult blood loss; during ESA treatment, assess baseline and periodic iron, total iron-binding capacity, and transferrin saturation or ferritin levels.

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events were observed in animal reproduction studies. In vitro studies suggest that recombinant erythropoietin does not cross the human placenta (Reisenberger 1997). Polyhydramnios and intrauterine growth retardation have been reported with use in women with chronic kidney disease (adverse effects also associated with maternal disease). Hypospadias and pectus excavatum have been reported with first trimester exposure (case report).

Recombinant erythropoietin alfa has been evaluated as adjunctive treatment for severe pregnancy associated iron deficiency anemia (Breymann 2001; Krafft 2009) and has been used in pregnant women with iron-deficiency anemia associated with chronic kidney disease (CKD) (Furaz-Czerpak 2012; Josephson 2007).

Amenorrheic premenopausal women should be cautioned that menstruation may resume following treatment with recombinant erythropoietin (Furaz-Czerpak 2012). Multidose formulations containing benzyl alcohol are contraindicated for use in pregnant women; if treatment during pregnancy is needed, single dose preparations should be used.

Women who become pregnant during treatment with epoetin alfa are encouraged to enroll in Amgen’s Pregnancy Surveillance Program (1-800-772-6436).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience injection site irritation, headache, nausea, vomiting, cough, bone pain, joint pain, muscle pain, muscle spasms, mouth sores, weight loss, or insomnia. Have patient report immediately to prescriber signs of severe cerebrovascular disease (change in strength on one side is greater than the other, difficulty speaking or thinking, change in balance, or vision changes), signs of DVT (edema, warmth, numbness, change in color, or pain in the extremities), signs of high blood sugar (confusion, fatigue, increased thirst, increased hunger, polyuria, flushing, fast breathing, or breath that smells like fruit), signs of low potassium (muscle pain or weakness, muscle cramps, or an abnormal heartbeat), angina, tachycardia, shortness of breath, excessive weight gain, swelling of arms or legs, difficulty swallowing, severe dizziness, passing out, confusion, seizures, severe headache, vision changes, severe loss of strength and energy, pale skin, coughing up blood, sweating a lot, cool or pale arms or legs, or abnormal gait (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.

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