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Special Alerts
Erythropoiesis-Stimulating Agents (ESAs): Dosing Recommendations Modified
June 2011
The U.S. Food and Drug Administration (FDA) is notifying healthcare professionals of revisions made to the prescribing information for the ESAs, epoetin alfa (Epogen®, Procrit®) and darbepoetin (Aranesp®), which include changes to the Boxed Warning, Warnings/Precautions, and Dosage/Administration sections of the labeling. The revised dosing modifications recommend more conservative dosing in patients with chronic kidney disease (CKD). The revisions were prompted by data in patients with CKD indicating an increased risk of cardiovascular events with ESA use. The ESA labels now include a warning that, in controlled trials, CKD patients experienced an increased risk of death, serious adverse cardiovascular reactions, and stroke when administered ESAs to a target hemoglobin >11 g/dL. To date, no clinical trial has identified a target hemoglobin level, ESA dose, or dosing guide that does not increase these risks.
ESA labels now recommend practitioners consider initiating ESA treatment in CKD patients when the hemoglobin is <10 g/dL. The target hemoglobin previously recommended in the labeling (target range of 10-12 g/dL in CKD patients) has been removed. There is currently no target hemoglobin recommended in the product labeling of ESAs. Instead the recommendation is to individualize dosing and use the lowest ESA dose necessary to decrease the need for red blood cell (RBC) transfusions, and to adjust the dose as appropriate.
The FDA is also providing the following additional information for healthcare professionals:
When treating CKD patients:
• ESAs dosed to a target hemoglobin >11 g/dL increase the risk of serious adverse cardiovascular events, without providing any proven additional patient benefit. No target hemoglobin level, ESA dose, or dosing guide has been studied that does not increase these risks.
• An ESA medication guide should be given to every patient (or patient representative) when an ESA is dispensed.
• Monitor hemoglobin levels at least weekly until stable when initiating or adjusting ESA therapy, then at least monthly.
• Patients not responding adequately over a 12-week escalation period are unlikely to have an improved response by further increasing the ESA dose, and the risks may be increased.
When treating CKD patients not receiving dialysis:
• Consider initiating ESA therapy only when the hemoglobin is <10 g/dL and both of the following are true:
- The rate at which the hemoglobin declines indicates the likelihood of RBC transfusions being required.
- Decreasing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal.
• If hemoglobin is >10 g/dL, decrease or interrupt the ESA dose and use the lowest dose of ESA sufficient to decrease the need for RBC transfusions.
When treating CKD patients on dialysis:
• Initiate ESA treatment when hemoglobin is <10 g/dL.
• If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the ESA dose.
Additional information may be found at http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm260641.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
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.
Brand Names: U.S.
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
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
Note: Epoetin 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
Note: In clinical trials (and one meta-analysis), epoetin has not demonstrated improved quality of life, fatigue, or well-being.
Use: Unlabeled
Treatment of 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. Polyhydramnios and intrauterine growth retardation have been reported with use in women with chronic kidney disease. Hypospadias and pectus excavatum have been reported (case report) with first trimester exposure. 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. Multidose formulations containing benzyl alcohol should not be used in pregnant women. Women who become pregnant during treatment with epoetin are encouraged to enroll in Amgen's Pregnancy Surveillance Program (1-800-772-6436).
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. Avoid the use of multidose vials in nursing women (due to the benzyl alcohol content).
Contraindications
Hypersensitivity to epoetin or any component of the formulation; uncontrolled hypertension; pure red cell aplasia (due to epoetin or other epoetin protein drugs); multidose vials contain benzyl alcohol and are contraindicated in neonates, infants, pregnant women, and nursing women
Warnings/Precautions
Boxed warnings:
• Cancer patients: See “Disease-related concerns” below.
• Cardiovascular events: See “Concerns related to adverse effects” below.
• Chronic kidney disease patients: See “Disease-related concerns” below.
• Perisurgery patients: See “Disease-related concerns” below.
• REMS program: See “Other warnings/precautions” 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: [U.S. Boxed Warning]: Erythropoiesis-stimulating agents (ESAs) increased the risk of serious cardiovascular events, thromboembolic events, stroke, 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.
• Pure red cell aplasia (PRCA): Cases of severe anemia and PRCA have been reported, predominantly in patients with chronic kidney disease 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 (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: [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 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: [U.S. 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 may require increased heparinization during dialysis to prevent clotting of the extracorporeal circuit.
• Hypertension/cardiovascular disease: 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 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]: 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 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 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 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:
• 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: [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 prior to each new epoetin course.
Adverse Reactions
>10%:
Cardiovascular: Hypertension (3% to 28%)
Central nervous system: Fever (10% to 42%), headache (5% to 18%)
Dermatologic: Pruritus (12% to 21%), 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%)
1% to 10%:
Cardiovascular: Deep vein thrombosis, edema, thrombosis
Central nervous system: Chills, depression, dizziness, insomnia
Dermatologic: Urticaria
Endocrine & metabolic: Hyperglycemia, hypokalemia
Gastrointestinal: Dysphagia, stomatitis, weight loss
Hematologic: Leukopenia
Local: Clotted vascular access
Neuromuscular & skeletal: Bone pain, muscle spasm, myalgia
Respiratory: Pulmonary embolism, respiratory congestion, upper respiratory infection
<1%, postmarketing, and/or case reports: Allergic reaction, anaphylactic reaction, angioedema, bronchospasm, erythema, hypersensitivity reactions, hypertensive encephalopathy, MI, microvascular thrombosis, neutralizing antibodies, porphyria, pure red cell aplasia (PRCA), renal vein thrombosis, retinal artery thrombosis, seizure, stroke, tachycardia, temporal vein thrombosis, thrombophlebitis, TIA, tumor progression
Metabolism/Transport Effects
None known.
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: Vd: 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 kidney disease: I.V.: 4-13 hours
Time to peak, serum: Chronic kidney disease: SubQ: 5-24 hours
Excretion: Feces (majority); urine (small amounts, 10% unchanged in normal volunteers)
Dosage
Anemia associated with chronic kidney disease: Individualize dosing and use the lowest dose necessary to reduce the need for RBC transfusions.
Chronic kidney disease patients
ON dialysis
(I.V. 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):
Children 1 month to 16 years: I.V., SubQ: Initial dose: 50 units/kg 3 times/week
Adults: I.V., SubQ: Initial dose: 50-100 units/kg 3 times/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 or other RBC transfusion-related risks; reduce dose or interrupt treatment if hemoglobin exceeds 10 g/dL):
Adults: I.V., SubQ: Initial dose: 50-100 units/kg 3 times/week
Dosage adjustments for chronic kidney disease patients (either on dialysis or not on dialysis):
If hemoglobin does not increase by >1 g/dL after 4 weeks: Increase dose by 25%; do not increase the dose more frequently than once every 4 weeks
If hemoglobin increases >1 g/dL in any 2-week period: Reduce dose by ≥25%; dose reductions can occur more frequently than once every 4 weeks; avoid frequent dosage adjustments
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 Hgb 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 ≥2 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: I.V.: 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%.
Adults: SubQ: Initial dose: 150 units/kg 3 times/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/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.
Children 8 months to 17 years (based on limited data): I.V., SubQ: Reported dosing range: 50-400 units/kg 2-3 times/week
Adults (with serum erythropoietin levels ≤500 mUnits/mL and zidovudine doses ≤4200 mg/week): I.V., SubQ: Initial: 100 units/kg 3 times/week; if hemoglobin does not increase after 8 weeks, increase dose by ~50-100 units/kg at 4-8 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): Adults: SubQ: Initial dose:
300 units/kg/day 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, beginning 21- , 14-, and 7 days before surgery, and on the day of surgery
Symptomatic anemia associated with MDS (unlabeled use): Adults: SubQ: 40,000-60,000 units 1-3 times/week (NCCN MDS guidelines v.2.2011)
Administration: I.V.
Patients with CKD 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 patients with CKD on hemodialysis; 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
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.
Reference Range
Zidovudine-treated HIV patients: Available evidence indicates patients with endogenous serum erythropoietin levels >500 mU/mL are unlikely to respond
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
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
Oncology Comment: The American Society of Clinical Oncology (ASCO) and American Society of Hematology (ASH) 2010 updates to the clinical practice guidelines for the use of erythropoiesis-stimulating agents (ESAs) in patients with cancer indicate that ESAs are most appropriate when used according to the parameters identified within the Food and Drug Administration (FDA) approved labeling for epoetin and darbepoetin (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.
The ASCO/ASH guidelines continue to recommend following the FDA approved dosing (and dosing adjustment) guidelines 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.
Prior to the initiation of ESAs, other sources of anemia (in addition to chemotherapy or underlying hematologic malignancy) should be investigated. Examinations recommended 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. Iron supplementation may be necessary
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. Interestingly, the mean pretransfusion hemoglobin was ~8.5 g/dL in both 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 resulted in no increase in 30-day mortality (restrictive 18.7% vs liberal 23.3%, p=0.11). In younger, less critically ill patients (age <55, APACHE <20), the liberal transfusion group had an increased mortality. Patients with acute myocardial infarction and unstable angina may benefit from the more liberal transfusion approach.
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 utilizing a strict transfusion trigger that was similar to that used in the Hebert transfusion trial. This transfusion practice was not done in prior trials evaluating erythropoietin in critically ill patients. 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 the trauma population given the findings in a posthoc subgroup analysis (Napolitano, 2008). 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. Medication can be given subcutaneously or intravenously. Obtain good medical history from patients as epoetin should not be used in history of uncontrolled hypertension, seizures, strokes, or MI. If no response in blood counts after 8 weeks of use, medication should be discontinued. All prescribers need to be enrolled in the ESA APPRISE program. Medication should be discontinued following chemotherapy. There is an increased risk of MI, stroke, thromboembolism, or mortality with attempts to raise Hgb over 11. Intravenous route should be used with patients on hemodialysis.
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): $40.28
3000 units/mL (1): $51.36
4000 units/mL (1): $63.45
10000 units/mL (2): $292.51
10000 units/mL (10): $1356.86
20000 units/mL (10): $2730.11
Solution (Procrit)
2000 units/mL (6): $243.31
3000 units/mL (6): $322.98
4000 units/mL (6): $476.15
10000 units/mL (6): $1086.03
20000 units/mL (1): $383.99
40000 units/mL (4): $3002.09
References
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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.
Macdougall IC, Roberts DE, Neubert P, et al, “Pharmacokinetics of Recombinant Human Erythropoietin in Patients on Continuous Ambulatory Peritoneal Dialysis,” Lancet, 1989, 1(8635):425-7.
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.
Napolitano LM, Fabian TC, Kelly KM, et al, "Improved Survival of Critically Ill Trauma Patients Treated With Recombinant Human Erythropoietin," J Trauma, 2008, 65(2):285-97.
National Comprehensive Cancer Network® (NCCN), “Practice Guidelines in Oncology™: Cancer- and Chemotherapy-Induced Anemia Version 1.2012.” Available at http://www.nccn.org/professionals/physician_gls/PDF/anemia.pdf
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International Brand Names
Lexi-Comp.com
Last full review/revision March 2012
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