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Special Alerts

Erythropoietin (Epogen®/Procrit®) and Darbepoetin (Aranesp®): Labeling Updates, Including Changes to Boxed Warning Regarding Use in Patients With Cancer - August 2008

The U.S. Food and Drug Administration (FDA), Amgen Inc, and Ortho Biotech have issued a “Dear Health Care Professional” letter alerting practitioners of revised labeling for erythropoiesis-stimulating agents (ESAs) (epoetin alfa [Epogen®, Procrit®] and darbepoetin alfa [Aranesp®]). The labeling for these products has been updated, including changes to the indications and boxed warnings, reflecting that ESAs are not indicated for patients receiving myelosuppressive therapy when the anticipated outcome is curative.

The FDA MedWatch alert can be found at http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA2

Erythropoiesis-Stimulating Agents (ESAs): Additional Information on Shortened Time to Tumor Progression and Increase in Mortality - Updated March 2008

The U.S. Food and Drug Administration (FDA) has issued an update to the November, 2007 alert on ESAs. This update includes information from two additional ESA studies in patients with chemotherapy-associated anemia. The studies provide further evidence of shortened time to tumor progression and increased mortality in cancer patients (breast, cervical, head and neck, lymphoid, and nonsmall cell lung cancer) who received ESAs; however, in the studies, the ESA doses were targeted to maintain hemoglobin levels ?12 g/dL. The FDA is planning a public advisory committee meeting to further discuss this new information as well as previous alert information.

Additional information may be found at http://www.fda.gov/bbs/topics/NEWS/2008/NEW01769.html and http://www.fda.gov/medwatch/safety/2008/safety08.htm#ESA

Erythropoiesis-Stimulating Agents (ESAs): Product Labeling Revised - November 2007

The U.S. Food and Drug Administration (FDA), Amgen Inc, and Ortho Biotech have issued a “Dear Health Care Professional” letter alerting practitioners of revised labeling for erythropoiesis-stimulating agents (ESAs) (epoetin alfa [Epogen®, Procrit®] and darbepoetin alfa [Aranesp®]). Labeling changes consist of strengthened boxed warnings, safety information, and revised dosing information. Updates also provide additional details and clarifications to the revisions made in the previous labeling update (March 2007) and include recommendations from FDA advisory committees on appropriate ESA use in cancer and chronic renal failure patients.

The boxed warning regarding use in cancer patients has been expanded to include the association of decreased overall survival and/or time to tumor progression observed in clinical studies using ESAs in patients with advanced breast, head and neck, lymphoid, and nonsmall cell lung cancer. This risk was noted in studies using ESAs dosed with the intent to achieve and maintain a target hemoglobin level of ?12 g/dL (not all studies achieved intended hemoglobin target). Based on this risk, as well as the risk of serious cardio- and thrombovascular events, new dosing guidelines in cancer patients recommend not exceeding a hemoglobin of 12 g/dL and using the lowest dose of ESAs to avoid red blood cell transfusions. The risk of increased mortality and tumor progression has not been excluded when ESAs are dosed to achieve hemoglobin levels <12 g/dL based on present data. Practitioners are reminded that ESA use is only appropriate in the treatment of anemia in cancer patients due to concomitant chemotherapy, and therapy should be discontinued following completion of chemotherapy.

Boxed warning changes concerning use in chronic renal failure patients include data from two studies showing an increased risk of death and serious cardiovascular events when ESAs were administered to achieve higher target hemoglobin compared with lower hemoglobin levels (13.5 vs 11.3 g/dL and 14 vs 10 g/dL). Dosing recommendations for chronic renal failure now specify a target hemoglobin range of 10-12 g/dL to achieve and maintain, including guidelines for increasing doses in patients not achieving recommended target hemoglobin range. Additional recommendations have been created for those patients unable to achieve the target hemoglobin range (despite appropriate titrations) with precautions against continuing to increase the dose and a consideration of ESA discontinuation.

Modifications have also been made to qualify particular parameters (eg, quality of life, fatigue, symptoms of anemia) as either not having been demonstrated or having been demonstrated in controlled clinical trials according to current standards. Medication guides are currently being developed to communicate the risks and benefits of ESAs for patients.

Additional information for healthcare providers, including the revised labeling, may be found at http://www.fda.gov/medwatch/safety/2007/safety07.htm#ESA2.

ALERT: U.S. Boxed Warning

The FDA-approved labeling includes a boxed warning. See Warnings/Precautions section and/or refer to product labeling for additional detail.

Medication Safety Issues

Sound-alike/look-alike issues:

Epoetin alfa may be confused with darbepoetin alfa, epoetin beta

International issues:

Epopen® [Spain] may be confused with EpiPen® which is a brand name for epinephrine in the U.S.

Pronunciation

(e POE e tin AL fa)

U.S. Brand Names

• Epogen®
• Procrit®

Index Terms

• rHuEPO-?
• EPO
• Erythropoiesis-Stimulating Agent (ESA)
• Erythropoietin
• NSC-724223

Generic Available

No

Canadian Brand Names

• Eprex®

Pharmacologic Category

• Colony Stimulating Factor

Pharmacologic Category Synonyms

• CSF

Use: Labeled Indications

Treatment of anemia (elevate/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), antineoplastic therapy (for nonmyeloid malignancies) due to concurrent chemotherapy; reduction of allogeneic blood transfusion for elective, noncardiac, nonvascular surgery

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

Use: Unlabeled/Investigational

Anemia associated with critical illness; anemia of prematurity

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-? does not cross the human placenta. Based on case reports, treatment with rHuEPO-? 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-? 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-? 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: See “Concerns related to adverse effects” below.

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

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

Concerns related to adverse effects:

• Cardiovascular events/mortality/thromboembolic events: [U.S. Boxed Warning]: ESAs increased the risk of cardiovascular events, thromboembolic events, 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.

• 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), Patients with loss of response should be evaluated for pure red cell aplasia with associated neutralizing antibodies to erythropoietin; discontinue treatment in patients with PRCA secondary to neutralizing antibodies to erythropoietin.

Disease-related concerns:

• Cancer patients: [U.S. Boxed Warning]: A shortened overall survival and/or time-to-tumor progression has been reported in studies with breast, cervical, head and neck, lymphoid, and nonsmall cell lung cancer patients receiving ESAs to a target hemoglobin of ?12 g/dL; risk has not been excluded when ESAs are dosed to achieve a target hemoglobin of <12 g/dL. Malignant cell lines and tumors may have surface receptors for erythropoietin; the possible role of epoetin in tumor cell proliferation is under investigation. [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.

• Chronic renal failure patients: [U.S. Boxed Warning]: An increased risk of death and serious cardiovascular events was reported in patients administered ESAs to target higher versus lower hemoglobin levels (13.5 vs 11.3 g/dL; 14 vs 10 g/dL) in two clinical studies; dosing should be individualized to achieve and maintain hemoglobin levels within 10-12 g/dL range. Chronic renal failure patients who exhibit an inadequate hemoglobin response to ESA therapy may be at a higher risk for cardiovascular 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.

• Hypertension/cardiovascular disease: Use with caution in patients with a history of hypertension. An excessive rate of rise of hematocrit may be possibly associated with the 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.

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

• Seizures: Use with caution in patients with a history of seizures. An excessive rate of rise of hematocrit 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.

Special populations:

• Pediatrics: Safety and efficacy in children <1 month of age have not been established.

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:

• Acute correction: Not recommended for acute correction of severe anemia or as a substitute for transfusion.

• 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.

• 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 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 (3% to 11%)

Central nervous system: Fever (29% to 51%), dizziness (<7% 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 (9% 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 (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, renal vein thrombosis, retinal artery thrombosis, 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.

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. 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.

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

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: 2-3 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% (a few patients)

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: SubQ, I.V.:

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. Do not increase dose more frequently than at 4-week intervals.

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)

Adults: 75 units/kg 3 times/week

Nondialysis patients:

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

Adults: Median 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: SubQ, I.V.: Limited data available; reported dosing range: 50-400 units/kg 2-3 times/week

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

Dosage adjustment:

Increase dose by 50-100 units/kg 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 3 times/week. If patients has not responded satisfactorily to a 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 approaches a level where transfusions may be required.

Cancer patient on chemotherapy: Treatment of patients with erythropoietin levels >200 mU/mL is not recommended. 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), 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 8 weeks of 3 times/week therapy) or (no increase in hemoglobin by ?1 g/dL after 4 weeks of once-weekly therapy), 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, obtain a hemoglobin to establish that it is >10 g/dL or ?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

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 dialysis: I.V. route preferred; may be administered I.V. bolus into the venous line after dialysis.

Patients with CRF not on dialysis: May be administered I.V. or SubQ

Administration: Other

SubQ:

Patients with CRF on dialysis: I.V. route preferred.

Patients with CRF not on dialysis: May be administered I.V. or SubQ

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.

Hemoglobin should be determined twice weekly until stabilization within the target range (30% to 36%), and twice weekly for at least 2-6 weeks after a dose increase. It may take 6-8 weeks to begin to see an effect and may take 16 weeks to see full therapeutic effect.

Reference Range

Guidelines should be based on the following figure or published literature

Guidelines for estimating appropriateness of endogenous EPO levels for varying levels of anemia via the EIA assay method: See figure. The reference range for erythropoietin in serum, for subjects with normal hemoglobin and hematocrit, is 4.1-22.2 mU/mL by the EIA method. Erythropoietin levels are typically inversely related to hemoglobin (and hematocrit) levels in anemias not attributed to impaired erythropoietin production.

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

Cancer chemotherapy patients: Treatment of patients with endogenous serum erythropoietin levels >200 mU/mL is not recommended

Serum EPO levels can be ordered routinely from clinical chemistry (red top serum separator tube).

Patient Education

Do not take any new prescription or OTC medications or herbal products during therapy unless approved by prescriber. 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. Do not make significant changes in your dietary iron without consulting prescriber. You may experience fever; headache; trouble sleeping; itching; skin pain; nausea; and/or vomiting, diarrhea, heartburn, and upper respiratory congestion. Contact prescriber if symptoms persist. Report signs or symptoms of edema (eg, swollen extremities, respiratory difficulty, rapid weight gain); onset of severe headache, unusual dizziness, or blurred vision; chest pain; leg pain and tenderness; muscular tremors or seizure activity; difficulty breathing, coughing, or congestion; or other adverse effects. Pregnancy/breast-feeding precautions: Inform prescriber if you are or intend to become pregnant. Consult prescriber if breast-feeding.

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

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 2005 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 results of laboratory tests prior to and on a regular scheduled basis during therapy (eg, blood chemistries, hemoglobin/hematocrit, serum ferritin, transferrin saturation); dosage adjustment and iron supplements may be necessary. Evaluate therapeutic effectiveness (according to purpose for use) and adverse response on a frequent basis during therapy (eg, hypertension, thrombotic events, edema, anemia). Teach patient proper use if self-administered (appropriate SubQ injection technique and syringe/needle disposal), possible side effects/appropriate interventions (importance of maintaining laboratory schedule), and adverse symptoms to report.

Oncology: Emetic Potential

Very low (<10%)

Oncology: Vesicant

No

Dosage Forms

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

Injection, solution [preservative free]:

Epogen®, 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 human albumin]

Injection, solution [with preservative]:

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

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

Solution (Epogen)

2000 units/mL (1): $36.71

3000 units/mL (1): $47.99

4000 units/mL (1): $53.50

10000 units/mL (2): $272.93

10000 units/mL (10): $1290.27

20000 units/mL (10): $2572.89

40000 units/mL (10): $5348.60

Solution (Procrit)

2000 units/mL (6): $182.98

3000 units/mL (6): $274.48

4000 units/mL (6): $363.90

10000 units/mL (6): $855.99

10000 units/mL (12): $1810.41

20000 units/mL (6): $1804.21

40000 units/mL (4): $2394.33

References

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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(8):914-24.

Brown KR, Carter W Jr, and Lombardi GE, “Recombinant Erythropoietin Overdose,” Am J Emerg Med, 1993, 11(6):619-21.

Brown MS and Keith JF 3rd, “Comparison Between Two and Five Doses a Week of Recombinant Human Erythropoietin for Anemia of Prematurity: A Randomized Trial,” Pediatrics, 1999, 104(2 Pt 1):210-5.

Corwin HL, Gettinger A, Pearl RG, et al, “Efficacy of Recombinant Human Erythropoietin in Critically Ill Patients: A Randomized Controlled Trial,” JAMA, 2002, 288(22):2827-35.

Cournoyer D, Toffelmire EB, Wells GA, et al, "Anti-Erythropoietin Antibody-Mediated Pure Red Cell Aplasia After Treatment With Recombinant Erythropoietin Products: Recommendations for Minimization of Risk," J Am Soc Nephrol, 2004, 15(10):2728-34.

Dellinger RP, Levy MM, Carlet JM, et al, “Surviving Sepsis Campaign: International Guidelines for Management of Severe Sepsis and Septic Shock: 2008,” Intensive Care Med, 2008, 34(1): 17-60. Available at http://www.survivingsepsis.org/system/files/images/2008_20International_20SSC_20Guidelines_1_.pdf

Donato H, Vain N, Rendo P, et al, “Effect of Early Versus Late Administration of Human Recombinant Erythropoietin on Transfusion Requirements in Premature Infants: Results of a Randomized, Placebo-Controlled, Multicenter Trial,” Pediatrics, 2000, 105(5):1066-72.

Drueke TB, Locatelli F, Clyne N, et al, “Normalization of Hemoglobin Level in Patients With Chronic Kidney Disease and Anemia,” N Engl J Med, 2006, 355(20): 2071-84.

Erslev AJ, “Erythropoietin,” N Engl J Med, 1991, 324(19):1339-44.

Feusner J and Hastings C, “Recombinant Human Erythropoietin in Pediatric Oncology: A Review,” Med Pediatr Oncol, 2002, 39(4):463-8.

Gareau R, Gagnon MG, Thellend C, et al, “Transferrin Soluble Receptor: A Possible Probe for Detection of Erythropoietin Abuse by Athletes,” Horm Metab Res, 1994, 26(6):311-2.

Goodnough LT, Price TH, Parvin CA, “The Indigenous Erythropoietin Response and the Erythropoietic Response to Blood Loss Anemia: The Effects of Age and Gender,” J Lab Clin Med, 1995, 126(1):57-64.

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(5):779-86.

Hebert PC, Wells G, Blajchman MA, et al, “A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group,” N Engl J Med, 1999, 340(6):409-17.

Henry DH and Thatcher N, “Patient Selection and Predicting Response to Recombinant Human Erythropoietin in Anemic Cancer Patients,” Semin Hematol, 1996, 33(1 Suppl 1):2-5.

Hunt SA, Abraham WT, Chin MH , et al, "ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure)," available at http://www.acc.org/qualityandscience/clinical/guidelines/failure/update/index.pdf.

Joosten E, Van Hove L, Lesaffre E, et al, “Serum Erythropoietin Levels in Elderly Inpatients With Anemia of Chronic Disorders and Iron Deficiency Anemia,” J Am Geriatr Soc, 1993, 41(12):1301-4.

Juul SE and Christensen RD, “Absorption of Enteral Recombinant Human Erythropoietin By Neonates,” Ann Pharmacother, 2003, 37(6):782-6.

Kharagjitsingh AV, Korevaar JC, Vandenbroucke JP, et al, "Incidence of Recombinant Erythropoietin (EPO) Hyporesponse, EPO-Associated Antibodies, and Pure Red Cell Aplasia in Dialysis Patients," Kidney Int, 2005, 68(3):1215-22.

Maier RF, Obladen M, Muller-Hansen I, et al, “Early Treatment With Erythropoietin Beta Ameliorates Anemia and Reduces Transfusion Requirements in Infants With Birth Weights Below 1000 g,” J Pediatr, 2002, 141(1):8-15.

Nafziger J, Pailla K, Luciani L, et al, “Decreased Erythropoietin Responsiveness to Iron Deficiency Anemia in the Elderly,” Am J Hematol, 1993, 43(3):172-6.

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National Kidney Foundation, “KDOQI Clinical Practice Guidelines and Clinical Practice Recommentaions for Anemia in Chronic Kidney Disease,” Am J Kidney Dis, 2007, 50(3):529-30. Available at http://www.kidney.org/professionals/kdoqi/pdf/KDOQI_finalPDF.pdf or http://www.kidney.org/professionals/KDOQI.

Naughton 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(5):464-8.

Ohls RK and Christensen, RD, “Stability of Human Recombinant Epoetin Alfa in Commonly Used Neonatal Intravenous Solutions,” Ann Pharmacother, 1996, 30(5):466-468.

Ohls RK, Ehrenkranz RA, Wright LL, et al, “Effects of Early Erythropoietin Therapy on the Transfusion Requirements of Preterm Infants Below 1250 Grams Birth Weight: A Multicenter, Randomized, Controlled Trial,” Pediatrics, 2001, 108(4):934-42.

Ohls RK, Veerman MW, and Christensen RD, “Pharmacokinetics and Effectiveness of Recombinant Erythropoietin Administered to Preterm Infants by Continuous Infusion in Total Parenteral Nutrition Solution,” J Pediatr, 1996, 128(4):518-23.

Phronmmintikul A, Haas SJ, Elsik M, et al, “Mortality and Target Haemoglobin Concentrations in Anaemic Patients with Chronic Kidney Disease Treated With Erythropoietin: A Meta-Analysis, Lancet, 2007, 369(9559):381-88.

Rhondeau SM, Christensen RD, Ross MP, et al, “Responsiveness to Recombinant Human Erythropoietin of Marrow Erythroid Progenitors From Infants With the Anemia of Prematurity,” J Pediatr, 1988, 112(6):935-40.

Rizzo JD, Somerfield MR, Hagerty LK, et al, “American Society of Hematology/American Society of Clinical Oncology 2007 Clinical Practice Guideline Update on the Use of Epoetin and Darbepoetin,” Blood, 2008, 111(1):25-41.

Rubins J, “Metastatic Renal Cell Carcinoma: Response to Treatment With Human Recombinant Erythropoietin,” Ann Intern Med, 1995, 122(9):676-7.

Shannon KM, Keith JF 3rd, Mentzer WC, et al, “Recombinant Human Erythropoietin Stimulates Erythropoiesis and Reduces Erythrocyte Transfusions in Very Low Birth Weight Preterm Infants,” Pediatrics, 1995, 95(1):1-8.

Sinai-Trieman L, Salusky IB, and Fine RN, “Use of Subcutaneous Recombinant Human Erythropoietin in Children Undergoing Continuous Cycling Peritoneal Dialysis,” J Pediatr, 1989, 114(4 Pt 1):550-4.

Singh AJ, Szczech L, Tang Kl, et al, “Correction of Anemia With Epoetin Alfa in Chronic Kidney Disease,” N Engl J Med, 2006, 355(20):2085-98.

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International Brand Names

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

Lexi-Comp.com

Last full review/revision August 2008