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Special Alerts

Epoetin Alfa Recall

September 2010

The U.S. Food and Drug Administration (FDA) and Amgen are notifying health care providers to a recall involving certain lots of epoetin alfa (Epogen® and Procrit®). The recalled lots may contain extremely thin glass flakes (lamellae) due to the interaction of the formulation with glass vials over the shelf life of the product.

Currently, no adverse events due to lamellae have been reported. Potentially, embolic, thrombotic and other vascular events (eg, phlebitis), may occur following I.V. administration, and foreign body granuloma, local injection site reactions, and increased immunogenicity may occur following SubQ administration of an injectable product with particulate matter.

The affected product lot numbers are available at www.epogen.com and www.procrit.com.

For additional information, refer to the following websites:

Amgen press release: http://www.fda.gov/Safety/Recalls/ucm227202.htm

FDA Safety alert: http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm227225.htm

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section for a concise summary of this information. For verbatim wording of the boxed warning, consult the product labeling or www.fda.gov.

Pronunciation

(e POE e tin AL fa)

Generic Available (U.S.)

No

Index Terms

• rHuEPO-α
• EPO
• Erythropoiesis-Stimulating Agent (ESA)
• Erythropoietin

Medication Guide

An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:

Epogen®: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM088591.pdf

Procrit®: http://www.fda.gov/downloads/Drugs/DrugSafety/UCM088988.pdf

REMS Components

Communication Plan; Elements to Assure Safe Use; Implementation System; Medication Guide

Noncancer-related uses: Medication Guide

Prescribing and Access Restrictions

As a requirement of the REMS program, access to this medication is restricted. Healthcare providers and hospitals must be enrolled in the ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program (866-284-8089; http://www.esa-apprise.com) to prescribe or dispense ESAs (ie, epoetin alfa, darbepoetin alfa) to patients with cancer.

U.S. Brand Names

• Epogen®
• Procrit®

Canadian Brand Names

• Eprex®

Pharmacologic Category

• Colony Stimulating Factor

Pharmacologic Category Synonyms

• CSF

Use: Labeled Indications

Treatment of anemia (elevate or maintain red blood cell level and decrease the need for transfusions) associated with HIV (zidovudine) therapy, chronic renal failure (including patients on dialysis and not on dialysis); reduction of allogeneic blood transfusion for elective, noncardiac, nonvascular surgery; treatment of anemia due to concurrent chemotherapy in patients with metastatic cancer (nonmyeloid malignancies) receiving chemotherapy for a minimum of 2 months

Note: Erythropoietin is not indicated for use in cancer patients under the following conditions:

• receiving hormonal therapy, therapeutic biologic products, or radiation therapy unless also receiving concurrent myelosuppressive chemotherapy

• receiving myelosuppressive therapy when the expected outcome is curative

• anemia due to other factors (eg, iron deficiency, folate deficiency, or gastrointestinal bleed)

Not intended for patients who require immediate correction of severe anemia or as a substitute for emergency transfusion.

Use: Unlabeled/Investigational

Treatment of anemia associated with critical illness; anemia of prematurity; symptomatic anemia in myelodysplastic syndrome (MDS)

Pregnancy Risk Factor

C

Pregnancy Considerations

Epoetin alfa has been shown to have adverse effects (decreased weight gain, delayed development, delayed ossification) in animal studies. Studies suggest that rHuEPO-α does not cross the human placenta. Based on case reports, treatment with rHuEPO-α may be an option in pregnant women with ESRD on dialysis. Amenorrheic premenopausal women should be cautioned that menstruation may resume following treatment with rHuEPO-α and contraception should be considered if pregnancy is to be avoided.

Lactation

Excretion in breast milk unknown/use caution

Breast-Feeding Considerations

When administered enterally to neonates (mixed with human milk or infant formula), rHuEPO-α did not significantly increase serum EPO concentrations. If passage via breast milk does occur, risk to a nursing infant appears low.

Contraindications

Hypersensitivity to albumin (human) or mammalian cell-derived products; uncontrolled hypertension

Warnings/Precautions

Boxed warnings:

• Cancer patients: See “Disease-related concerns” below.

• Cardiovascular events/mortality/thromboembolic events/stroke: See “Concerns related to adverse effects” below.

• Chronic renal failure patients: See “Disease-related concerns” below.

• ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program: See “Other warnings/precautions” below.

• Perisurgery patients: See “Disease-related concerns” below.

Concerns related to adverse effects:

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

• Cardiovascular events/mortality/thromboembolic events/stroke: [U.S. Boxed Warning]: Erythropoiesis-stimulating agents (ESAs) increased the risk of serious cardiovascular events, thromboembolic events, stroke, and mortality in clinical studies; a rapid rise in hemoglobin (>1 g/dL over 2 weeks) or maintaining higher hemoglobin levels may contribute to these risks. Patients treated with epoetin may require increased heparinization during dialysis to prevent clotting of the artificial kidney.

• Pure red cell aplasia (PRCA): Cases of severe anemia and PRCA have been reported, predominantly in patients with CRF receiving SubQ epoetin (the I.V. 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 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: [U.S. 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 nonsmall 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. [U.S. 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 chemotherapy; discontinue ESA following completion of the chemotherapy course. ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is curative. 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 has not been demonstrated in controlled clinical trials.

• Chronic renal failure patients: [U.S. Boxed Warning]: An increased risk of death, serious cardiovascular events, and stroke was reported in patients administered ESAs to target hemoglobin levels ≥13 g/dL; dosing should be individualized to achieve and maintain hemoglobin levels within 10-12 g/dL range. Hemoglobin rising >1 g/dL in a 2-week period may contribute to the risk. Chronic renal failure 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.

• Hematologic diseases: Safety and efficacy in patients with underlying hematologic diseases have not been established, including hypercoagulation disorders and sickle cell disease.

• Hypertension/cardiovascular disease: Use with caution in patients with a history of hypertension. An excessive rate of rise of hemoglobin is associated with hypertension or exacerbation of hypertension; decrease the epoetin 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: [U.S. Boxed Warning]: Epoetin alfa increased the rate of DVT in patients not receiving anticoagulant prophylaxis; consider DVT prophylaxis in surgery patients. Increased mortality was also observed in patients undergoing coronary artery bypass surgery who received epoetin alfa; these deaths were associated with thrombotic events. Epoetin is not approved for reduction of red blood cell transfusion in patients undergoing cardiac or vascular surgery and is not indicated for anemic patients willing to donate autologous blood.

• Porphyria: Use caution with porphyria, exacerbation of porphyria has been reported in patients with chronic renal failure.

• Seizures: Seizures have been reported in clinical trials for chronic renal failure; use with caution in patients with a history of seizures. The risk of seizures is increased in the first 90 days of therapy. An excessive rate of rise of hemoglobin may be possibly associated with the exacerbation of seizures; decrease the epoetin dose if the hemoglobin increase exceeds 1 g/dL in any 2-week period.

• Severe anemia or acute blood loss: Due to the delayed onset of erythropoiesis, epoetin 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: Multidose vials contain benzyl alcohol which has been associated with "gasping syndrome" in neonates.

Other warnings/precautions:

• Appropriate use: Hemoglobin levels should not exceed a target range of 10-12 g/dL and should not rise >1 g/dL per 2-week time period during therapy in any patient.

• ESA APPRISE (Assisting Providers and Cancer Patients with Risk Information for the Safe use of ESAs) Oncology Program: [U.S. Boxed Warning]: Because of the risks of decreased survival and increased risk of tumor growth or progression, all healthcare providers and hospitals are required to enroll and comply with the ESA APPRISE Oncology Program prior to prescribing or dispensing ESAs to cancer patients. Prescribers and patients will have to provide written documentation of discussed risks.

• 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 (aluminum toxicity, inflammatory conditions, infections). Poor response to therapy should prompt evaluation of potential factors impairing erythropoiesis, as well as possible malignant processes, occult blood loss, hemolysis, 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%.

Adverse Reactions

>10%:

Cardiovascular: Hypertension (5% to 24%), thrombotic/vascular events (coronary artery bypass graft surgery: 23%), edema (6% to 17%), deep vein thrombosis (≤11%)

Central nervous system: Fever (29% to 51%), dizziness (5% to 21%), insomnia (13% to 21%), headache (10% to 19%)

Dermatologic: Pruritus (14% to 22%), skin pain (4% to 18%), rash (≤16%)

Gastrointestinal: Nausea (11% to 58%), constipation (42% to 53%), vomiting (8% to 29%), diarrhea (6% to 21%), dyspepsia (7% to 11%)

Genitourinary: Urinary tract infection (3% to 12%)

Local: Injection site reaction (<10% to 29%)

Neuromuscular & skeletal: Arthralgia (≤11%), paresthesia (≤11%)

Respiratory: Cough (≤18%), congestion (≤15%), dyspnea (13% to 14%), upper respiratory infection (≤11%)

1% to 10%:

Central nervous system: Seizure (1% to 3%)

Local: Clotted vascular access (7%)

<1%, postmarketing, and/or case reports: Allergic reaction, anemia associated with neutralizing antibodies (severe; with or without other cytopenias), CVA, flu-like syndrome, hyperkalemia, hypersensitivity reactions, hypertensive encephalopathy, microvascular thrombosis, MI, myalgia, neutralizing antibodies, pulmonary embolism, pure red cell aplasia (PRCA), renal vein thrombosis, retinal artery thrombosis, stroke, tachycardia, temporal vein thrombosis, thrombophlebitis, thrombosis, TIA, urticaria

Drug Interactions

There are no known significant interactions.

Storage

Vials should be stored at 2°C to 8°C (36°F to 46°F); do not freeze or 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: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.

Reconstitution

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

Compatibility

Stable in D₁₀W with albumin 0.05%, D₁₀W with albumin 0.1%; incompatible with D₁₀W with albumin 0.01%, D₁₀W, NS; variable stability (consult detailed reference) in TPN.

Mechanism of Action

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.

Pharmacodynamics/Kinetics

Onset of action: Several days

Peak effect: Hemoglobin level: 2-6 weeks

Distribution: V_d: 9 L; rapid in the plasma compartment; concentrated in liver, kidneys, and bone marrow

Metabolism: Some degradation does occur

Bioavailability: SubQ: ~21% to 31%; intraperitoneal epoetin: 3% (Macdougall, 1989)

Half-life elimination: Cancer: SubQ: 16-67 hours; Chronic renal failure: I.V.: 4-13 hours

Time to peak, serum: Chronic renal failure: SubQ: 5-24 hours

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

Dosage

Note: Hemoglobin levels should not exceed 12 g/dL and should not rise >1 g/dL per 2-week time period during therapy in any patient.

Chronic renal failure patients: Individualize dosing to achieve and maintain hemoglobin levels between 10-12 g/dL. Hemoglobin levels should not exceed 12 g/dL. Note: I.V. route is preferred for hemodialysis patients.

Children: I.V., SubQ: Initial dose: 50 units/kg 3 times/week

Adults: I.V., SubQ: Initial dose: 50-100 units/kg 3 times/week

Dosage adjustment in Children and Adults: I.V., SubQ:

Decrease dose by 25%: If hemoglobin approaches 12 g/dL or hemoglobin increases >1 g/dL in any 2-week period. If hemoglobin continues to increase, temporarily discontinue therapy until hemoglobin begins to decrease, then resume therapy with a ~25% reduction from previous dose.

Increase dose by 25%: If hemoglobin <10 g/dL and does not increase by 1 g/dL after 4 weeks of therapy (with adequate iron stores) or hemoglobin decreases below 10 g/dL. If transferrin saturation >20%, may increase epoetin dose. Do not increase dose more frequently than at 4-week intervals, unless clinically indicated (hemoglobin response time for dose increases may be 2-6 weeks).

Inadequate or lack of response: If patient does not attain target hemoglobin range of 10-12 g/dL after appropriate dose titrations over 12 weeks:

Do not continue to increase dose and use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions and evaluate patient for other causes of anemia.

Monitor hemoglobin closely thereafter, and if responsiveness improves, may resume making dosage adjustments as recommended above. If responsiveness does not improve and recurrent red blood cell transfusions continue to be needed, discontinue therapy.

Maintenance dose: Individualize to target hemoglobin range of 10-12 g/dL; limit additional dosage increases to every 4 weeks (or longer)

Dialysis patients: Median dose:

Children: 167 units/kg/week (hemodialysis) or 76 units/kg/week (peritoneal dialysis), in 2-3 divided doses per week

Adults: 75 units/kg 3 times/week

Nondialysis patients:

Children: Dosing range: 50-250 units/kg 1-3 times/week

Adults: Dosing range: 75-150 units/kg/week

Zidovudine-treated, HIV-infected patients (patients with erythropoietin levels >500 mU/mL are unlikely to respond): 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: I.V., SubQ: Limited data available; reported dosing range: 50-400 units/kg 2-3 times/week

Adults (with serum erythropoietin levels ≤500 mU/mL and zidovudine doses ≤4200 mg/week): I.V., SubQ: 100 units/kg 3 times/week for 8 weeks

Dosage adjustment:

Increase dose in increments of 50-100 units/kg administered 3 times/week: If response is not satisfactory in terms of reducing transfusion requirements or increasing hemoglobin after 8 weeks of therapy. Evaluate response every 4-8 weeks thereafter, and adjust the dose accordingly by 50-100 units/kg increments administered 3 times/week. If patients has not responded satisfactorily to 300 units/kg/dose 3 times/week, a response to higher doses is unlikely.

Withhold dose: If hemoglobin exceeds 12 g/dL. Resume treatment with a 25% dose reduction when hemoglobin drops below 11 g/dL

Cancer patient on chemotherapy: Treatment of patients with erythropoietin levels >200 mU/mL is not recommended by the manufacturer. Titrate dosage to use the minimum effective dose that will maintain a hemoglobin level sufficient to avoid red blood cell transfusions. Do not initiate therapy if hemoglobin ≥10 g/dL. Discontinue erythropoietin following completion of chemotherapy.

Children: I.V.: 600 units/kg once weekly (maximum: 40,000 units)

Dosage adjustment:

Increase dose: If response is not satisfactory after a sufficient period of evaluation (no increase in hemoglobin by ≥1 g/dL after 4 weeks of once-weekly therapy, in the absence of RBC transfusion), the dose may be increased every 4 weeks (or longer) to 900 units/kg/week; maximum 60,000 units. If patient does not respond, a response to higher doses is unlikely.

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

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

Discontinue: If after 8 weeks of therapy there is no response (ie, increased hemoglobin levels) or transfusions still required.

Adults: SubQ: Initial dose: 150 units/kg 3 times/week or 40,000 units once weekly; commonly used doses range from 10,000 units 3 times/week to 40,000-60,000 units once weekly.

Dosage adjustment:

Increase dose: If response is not satisfactory after a sufficient period of evaluation (no reduction in transfusion requirements or increase in hemoglobin after 4 weeks of 3 times/week therapy) or (no increase in hemoglobin by ≥1 g/dL after 4 weeks of once-weekly therapy, in the absence of RBC transfusion), the dose may be increased every 4 weeks (or longer) to 300 units/kg 3 times/week, or when dosed weekly, increased all at once to 60,000 units weekly. If patient does not respond, a response to higher doses is unlikely.

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

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

Discontinue: If after 8 weeks of therapy there is no response (ie, increased hemoglobin levels) or transfusions still required.

Surgery patients: Prior to initiating treatment, measure hemoglobin to establish that it is >10 g/dL and ≤13 g/dL: Adults: SubQ: Initial dose: 300 units/kg/day for 10 days before surgery, on the day of surgery, and for 4 days after surgery

Alternative dose: 600 units/kg in once weekly doses (21, 14, and 7 days before surgery) plus a fourth dose on the day of surgery

Anemia of critical illness (unlabeled use): Adults: SubQ: 40,000 units once weekly

Symptomatic anemia associated with MDS (unlabeled use): Adults: SubQ: 40,000-60,000 units 1-3 times/week (NCCN MDS guidelines v.2.2010)

Anemia of prematurity (unlabeled use): Infants: I.V., SubQ: Dosing range: 500-1250 units/kg/week; commonly used dose: 250 units/kg 3 times/week; supplement with oral iron therapy 3-8 mg/kg/day

Dosage adjustment in renal impairment: The National Kidney Foundation Clinical Practice Guideline for Anemia in Chronic Kidney Disease: 2007 Update of Hemoglobin Target (September, 2007) recommend hemoglobin levels in the range of 11-12 g/dL for dialysis and nondialysis patients receiving ESAs; hemoglobin levels should not be >13 g/dL.

Hemodialysis: Supplemental dose is not necessary. I.V. route is preferred for hemodialysis patients.

Peritoneal dialysis: Supplemental dose is not necessary.

Administration: I.V.

Patients with CRF on hemodialysis: I.V. route preferred; it may be administered into the venous line at the end of the dialysis procedure

Note: SubQ administration is the preferred route in other patient populations.

Administration: Other

SubQ: SubQ is the preferred route of administration except in hemodialysis patients; 1:1 dilution with bacteriostatic NS (containing benzyl alcohol) acts as a local anesthetic to reduce pain at the injection site.

Administration: I.V. Detail

pH: 6.6-7.2 (single dose vial); 5.8-6.4 (multidose vial)

Monitoring Parameters

Blood pressure; hemoglobin, CBC with differential and platelets, transferrin saturation and ferritin, serum chemistry (CRF patients)

Suggested tests to be monitored and their frequency: See table.

Reference Range

Zidovudine-treated HIV patients: Available evidence indicates patients with endogenous serum erythropoietin levels >500 mU/mL are unlikely to respond

Cancer chemotherapy patients: Measurement of endogenous serum erythropoietin levels in patients with cancer is generally not recommended (NCCN Cancer- and Chemotherapy-Induced Anemia Guidelines, v2.2010). Treatment of patients with endogenous serum erythropoietin levels >200 mU/mL is not recommended according to the manufacturer.

Patient Education

If self-administered, follow exact directions for injection and needle disposal. You will require frequent blood tests to determine appropriate dosage and reduce potential for severe adverse effects; maintaining laboratory testing schedule is vital. Report skin rash; difficulty swallowing; onset of severe headache, unusual dizziness, or blurred vision; chest pain; muscular tremors or seizure activity; or difficulty breathing.

Geriatric Considerations

There is limited information about the use of epoetin alfa in the elderly. Endogenous erythropoietin secretion has been reported to be decreased in elderly with normocytic or iron deficiency anemias or those with a serum hemoglobin concentration <12 g/dL; one study did not find such a relationship in the elderly with chronic anemia. A blunted erythropoietin response to anemia has been reported in patients with cancer, rheumatoid arthritis, and AIDS.

Additional Information

Factors limiting response to epoetin alfa: Delayed onset of erythropoiesis (2-6 weeks to increase hemoglobin), iron deficiency (most patients require iron supplementation); underlying infection, inflammatory or malignant process; blood loss (occult), underlying hematologic disease (thalassemia, refractory anemia, MDS); vitamin deficiency (folic acid or cyanocobalamin), hemolysis, aluminum overload, osteitis fibrosa cystica, and PRCA

Oncology Comment: The American Society of Hematology (ASH) and American Society of Clinical Oncology (ASCO) 2007 updates to the clinical practice guidelines for the use of erythropoiesis-stimulating agents (ESAs) indicate that ESAs are most appropriate when used according to the dosage parameters within the Food and Drug Administration (FDA) approved labeling for epoetin and darbepoetin (Rizzo, 2008). While the previous guidelines addressed only the use of epoetin, the 2007 guidelines also address the use of darbepoetin, which is assessed as being equivalent to epoetin with respect to safety and efficacy. When used as an option for the treatment of chemotherapy-associated anemia (to increase hemoglobin and decrease red blood cell transfusions), therapy with ESAs should begin as the hemoglobin level approaches or falls below 10 g/dL. The ASH/ASCO guidelines recommend following the FDA approved dosing (and dosing adjustment) guidelines and target hemoglobin ranges as alternate dosing and schedules have not demonstrated consistent differences in effectiveness with regard to hemoglobin response. In patients who do not have a response within 6-8 weeks (hemoglobin rise <1-2 g/dL or no reduction in transfusions) ESA therapy should be discontinued.

The guidelines note that patients with an increased risk of thromboembolism (generally includes previous history of thrombosis, surgery, and/or prolonged periods of immobilization) and patients receiving concomitant medications that may increase thromboembolic risk, should begin ESA therapy only after careful consideration. With the exception of low-risk myelodysplasia-associated anemia (which has evidence supporting the use of ESAs without concurrent chemotherapy), the guidelines do not support the use of ESAs in the absence of concurrent chemotherapy.

Anesthesia and Critical Care Concerns/Other Considerations

Evidence-Based Information:

Routine Use in Critically-Ill Patients: A prospective, randomized, double-blind, placebo-controlled, multicenter trial was performed with critically-ill patients assessing the efficacy of recombinant human erythropoietin in reducing red blood cell transfusions (Corwin, 2002). Patients were enrolled from December 1998 through June 2001. Over 1300 ICU (medical, surgical, or medical/surgical) patients were randomized to receive placebo or 40,000 units of erythropoietin subcutaneously on ICU day 3 and then weekly for a total of 3 doses for patients who remained in the hospital. Inclusion criteria included ICU stay for 3 days, age >18 years, and hematocrit <38%. Exclusion criteria were extensive and included acute ischemic heart disease, acute gastrointestinal bleed, and renal failure with hemodialysis. Each patient's physician determined the need for red blood cell transfusion. Results: The mean baseline hemoglobin was 9.97 g/dL in each group. Patients receiving erythropoietin were less likely to receive transfusions. The median number of units transfused per patient in the placebo group was 2 and in the erythropoietin group was 1 (p<0.001). The erythropoietin group had a 9.9% absolute reduction in RBC transfusions during 28 days (p<0.001, OR 0.67, CI 0.54-0.83). Mortality and adverse clinical events were not significantly different between groups. The authors concluded that weekly administration of erythropoietin in critically-ill patients reduces red blood cell transfusions and increases hemoglobin. The authors also suggest that further study is needed to determine if use of erythropoietin results in improved clinical outcomes.

A restrictive transfusion trial was published after the above Corwin trial was underway (Hebert, 1999). Hebert and his group evaluated a restrictive transfusion strategy (transfuse if hemoglobin <7 g/dL to maintain between 7 and 9 g/dL) versus a liberal strategy (transfuse if hemoglobin <10 g/dL to maintain between 10 and 12 g/dL). Inclusion criteria included anticipated ICU stay >24 hours, hemoglobin ≤9 g/dL with 72 hours of ICU admission, and euvolemia after initial treatment. Exclusion criteria included chronic anemia, active bleeding, or admission after a routine cardiac surgical procedure. The restrictive approach to transfusion was at least as effective as and possibly superior to a liberal transfusion policy in critically-ill patients. The exception to this may be patients with acute myocardial infarction and unstable angina.

More recently, Corwin, et al (2007) once again evaluated the use of recombinant human erythropoietin in the critically ill. In this prospective, randomized, placebo-controlled trial, 1460 medical, surgical, or trauma patients were enrolled between December, 2003 and June, 2006. Patients received either subcutaneous erythropoietin 40,000 units or placebo once weekly for a maximum of 3 doses and were followed for 140 days. The primary endpoint of the study was the percentage of patients who received a red cell transfusion between days 1 and 29. Secondary endpoints included the number of red cell units transfused between days 1 and 29, mortality at day 29 and day 140, and the change in hemoglobin concentration from baseline to day 29. Patients were evaluated for inclusion into the study if they remained in that ICU for 2 days. Inclusion criteria were age >18 years and hemoglobin concentration <12 g/dL. Exclusion criteria were extensive and included acute ischemic heart disease during the ICU stay, acute gastrointestinal bleed, hemodialysis, and patients at risk for thrombosis (history of pulmonary embolism, deep venous thrombosis, ischemic stroke, other arterial or venous thrombosis). Red cell transfusions targeted hemoglobin concentrations between 7 and 9 g/dL, but the need for transfusion was determined by the treating physician (this is more consistent with clinical practice after the Hebert trial was published and different than the previous Corwin trial). Results: The mean baseline hemoglobin for each group was 9.6 g/dL. The use of erythropoietin did not significantly decrease the need for red cell transfusion (46.0% in the erythropoietin group transfused vs 48.3% in the placebo group, p=0.34). The hemoglobin concentration at day 29 increased more in the erythropoietin group compared to placebo (1.6 ± 2.0 g/dL vs 1.2 ± 1.8 g/dL, p<0.001); however, by day 42 the hemoglobin concentrations in both groups were similar. Mortality at day 29 was significantly lower in the group receiving erythropoietin (8.5% vs 11.4%, p=0.02) from the Kaplan-Meier estimate, but no difference was seen in the Cox model in the overall population. Only in the trauma subset was mortality at day 29 significantly lower in the erythropoietin group (3.5% vs 6.6%, p=0.04). At day 140, mortality was not significantly lower in the erythropoietin group. Thrombotic events (eg, DVT and myocardial infarction) were significantly higher in the erythropoietin group as compared to placebo and appeared to be dose-related (16.5% vs 11.5%, p=0.008, HR 1.41, CI 1.06-1.86). However, upon further analysis those patients who did not receive heparin at baseline developed these events more frequently. There was no difference in length of stay or the use of mechanical ventilation between groups. The authors concluded that although erythropoietin does not reduce the incidence of red cell transfusion in critically-ill patients, it may reduce mortality in trauma patients. Further investigation is required to define erythropoietin's role in this population. The routine use of erythropoietin in critically-ill, nontraumatic surgical or medical patients is not supported by this study.

The 2008 Surviving Sepsis Campaign guidelines do not recommend erythropoietin as a treatment for anemia associated with severe sepsis, but suggest that it may be used when septic patients have other therapeutic indications (Grade 1B).

Cardiovascular Considerations

The ACC/AHA 2009 Heart Failure Guidelines suggest that the benefit of enhancing erythropoiesis in these patients is not established. Although some small studies have shown a benefit from erythropoietin and iron in mild anemia in heart failure, further investigation is required evaluating the risks and benefits.

Dental Health: Effects on Dental Treatment

No significant effects or complications reported

Dental Health: Vasoconstrictor/Local Anesthetic Precautions

No information available to require special precautions

Mental Health: Effects on Mental Status

Sedation is common; may cause dizziness

Mental Health: Effects on Psychiatric Treatment

None reported

Nursing: Physical Assessment/Monitoring

Evaluate history of hypertension or seizures and potential risk for thromboembolism prior to beginning therapy. Blood pressure should be monitored closely and controlled during therapy. If administered by intravenous infusion, lines should be monitored closely for possible clotting. Assess blood chemistries, hemoglobin/hematocrit, serum ferritin, and transferrin saturation prior to and on a regular basis during therapy; dosage adjustment and iron supplements may be necessary. Monitor for hypertension, thrombotic events, edema, and anemia. Serious allergic or anaphylactic reactions may require discontinuation of treatment. Teach patient proper SubQ injection technique and syringe/needle disposal.

Dosage Forms

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

Injection, solution:

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

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

Injection, solution [preservative free]:

Epogen®: 2000 units/mL (1 mL); 3000 units/mL (1 mL); 4000 units/mL (1 mL); 10,000 units/mL (1 mL) [contains albumin (human)]

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) [contains albumin (human)]

Pricing: U.S. (www.drugstore.com)

Solution (Epogen)

2000 units/mL (1): $39.99

3000 units/mL (1): $50.99

4000 units/mL (1): $62.99

10000 units/mL (2): $290.39

10000 units/mL (10): $1347.04

20000 units/mL (10): $2685.95

40000 units/mL (10): $5456.14

Solution (Procrit)

2000 units/mL (6): $213.99

3000 units/mL (6): $299.99

4000 units/mL (6): $429.98

10000 units/mL (6): $1013.95

20000 units/mL (1): $359.99

40000 units/mL (4): $2799.98

References

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International Brand Names

• Binocrit (GB)
• Efotin (PH)
• EPIAO (TH)
• Epogen (PH)
• Epokine (PH)
• Eposino (PH)
• Eposis (KP, TH)
• Eprex (AE, AR, AU, BB, BD, BE, BG, BH, BM, BS, BZ, CH, CR, CY, CZ, DK, DO, EE, EG, ES, FI, FR, GB, GR, GT, GY, HK, HN, HR, HU, IL, IN, IQ, IR, IT, JM, JO, KW, LB, LY, MX, MY, NI, NL, NO, OM, PA, PE, PK, PL, PY, QA, RU, SA, SE, SG, SR, SV, SY, TR, TT, TW, UY, VE, YE)
• Erypo (AT, DE)
• Espo (CL, JP)
• Espogen (TH)
• Hemapo (ID)
• Hypercrit (BR, CN)
• Neorecormon (ES, IE, PT)
• Renogen (PH, TH)
• Yi Pu Li (CL)

Lexi-Comp.com

Last full review/revision March 2011

Content last modified March 2011