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Epogen(epoetin alfa)injection, for intravenous or subcutaneous
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Epogen safely and effectively. See full prescribing information for Epogen.
Epogen ® (epoetin alfa)
injection, for intravenous or subcutaneous use
Initial U.S. Approval: 1989
WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE
See full prescribing information for complete boxed warning.
Chronic Kidney Disease:
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In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL (5.1).
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No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks.
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Use the lowest Epogen dose sufficient to reduce the need for red blood cell (RBC) transfusions (5.1).
Cancer:
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ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers (Table 2, 5.3).
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Prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense Epogen to patients with cancer (5.2).
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Use the lowest dose to avoid RBC transfusions (2.4).
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Use ESAs only for anemia from myelosuppressive chemotherapy (1.5).
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ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.5).
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Discontinue following the completion of a chemotherapy course (2.4).
Perisurgery:
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Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended (5.1).
RECENT MAJOR CHANGES
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Dosage and Administration:
Patients on Cancer Chemotherapy (2.4)
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12/2013 |
INDICATIONS AND USAGE
Epogen is an erythropoiesis-stimulating agent (ESA) indicated for:
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Treatment of anemia due to
- Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis (1.1).
- Zidovudine in HIV-infected patients (1.2).
- The effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy (1.3).
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Reduction of allogeneic RBC transfusions in patients undergoing elective, noncardiac, nonvascular surgery (1.4).
Limitations of Use
Epogen has not been shown to improve quality of life, fatigue, or patient well-being (1.5).
Epogen is not indicated for use:
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In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy (1.5).
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In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure (1.5).
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In patients scheduled for surgery who are willing to donate autologous blood (1.5).
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In patients undergoing cardiac or vascular surgery (1.5).
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As a substitute for RBC transfusions in patients who require immediate correction of anemia (1.5).
DOSAGE AND ADMINISTRATION
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CKD Patients: Initial dose: 50 to 100 Units/kg 3 times weekly (adults) and 50 Units/kg 3 times weekly (children on dialysis). Individualize maintenance dose. Intravenous route recommended for patients on hemodialysis (2.2).
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Zidovudine-treated HIV-infected Patients: 100 Units/kg 3 times weekly (2.3).
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Cancer Patients on Chemotherapy: 40,000 Units weekly or 150 Units/kg 3 times weekly (adults); 600 Units/kg intravenously weekly (children ≥ 5 years) (2.4).
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Surgery Patients: 300 Units/kg per day daily for 15 days or 600 Units/kg weekly (2.5).
DOSAGE FORMS AND STRENGTHS
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Single-dose vial: 2000, 3000, 4000, and 10,000 Units/1 mL (3)
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Multidose vial containing benzyl alcohol: 20,000 Units/2 mL and 20,000 Units/1 mL (3)
CONTRAINDICATIONS
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Uncontrolled hypertension (4)
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Pure red cell aplasia (PRCA) that begins after treatment with Epogen or other erythropoietin protein drugs (4)
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Serious allergic reactions to Epogen (4)
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Use of the multidose vials in neonates, infants, pregnant women, and nursing mothers (4)
WARNINGS AND PRECAUTIONS
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Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit (5.1 and 14.1). Use caution in patients with coexistent cardiovascular disease and stroke (5.1).
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Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer (5.2 and 5.3).
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Hypertension: Control hypertension prior to initiating and during treatment with Epogen (5.4).
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Seizures: Epogen increases the risk for seizures in patients with CKD (5.5). Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms (5.5).
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PRCA: If severe anemia and low reticulocyte count develop during Epogen treatment, withhold Epogen and eva luate for PRCA (5.7).
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Patients with CKD: Adverse reactions in ≥ 5% of Epogen-treated patients in clinical studies were hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion, and upper respiratory tract infection (6.1).
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Zidovudine-treated HIV-infected Patients: Adverse reactions in ≥ 5% of Epogen-treated patients in clinical studies were pyrexia, cough, rash, and injection site irritation (6.1).
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Cancer Patients on Chemotherapy: Adverse reactions in ≥ 5% of Epogen-treated patients in clinical studies were nausea, vomiting, myalgia, arthralgia, stomatitis, cough, weight decrease, leukopenia, bone pain, rash, hyperglycemia, insomnia, headache, depression, dysphagia, hypokalemia, and thrombosis (6.1).
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Surgery Patients: Adverse reactions in ≥ 5% of Epogen-treated patients in clinical studies were nausea, vomiting, pruritus, headache, injection site pain, chills, deep vein thrombosis, cough, and hypertension (6.1).
To report SUSPECTED ADVERSE REACTIONS, contact Amgen Medical Information at 1-800-77-AMGEN (1-800-772-6436) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
USE IN SPECIFIC POPULATIONS
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Pregnancy, nursing mothers, neonates, and infants: Use single-dose vials only and do not mix with benzyl alcohol. Based on animal data, Epogen may cause fetal harm. Pregnancy Surveillance Program is available (8.1, 8.3, and 8.4).
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Pediatric Use: Safety and effectiveness have not been established in CKD patients undergoing dialysis who are less than 1 month old, pediatric patients with cancer less than 5 years old, pediatric patients with CKD not on dialysis, and pediatric patients with HIV infection (8.4).
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 6/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
1.1 Anemia Due to Chronic Kidney Disease
Epogen is indicated for the treatment of anemia due to chronic kidney disease (CKD), including patients on dialysis and not on dialysis to decrease the need for red blood cell (RBC) transfusion.
1.2 Anemia Due to Zidovudine in HIV-infected Patients
Epogen is indicated for the treatment of anemia due to zidovudine administered at ≤ 4200 mg/week in HIV-infected patients with endogenous serum erythropoietin levels of ≤ 500 mUnits/mL.
1.3 Anemia Due to Chemotherapy in Patients With Cancer
Epogen is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy.
1.4 Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery
Epogen is indicated to reduce the need for allogeneic RBC transfusions among patients with perioperative hemoglobin > 10 to ≤ 13 g/dL who are at high risk for perioperative blood loss from elective, noncardiac, nonvascular surgery. Epogen is not indicated for patients who are willing to donate autologous blood pre-operatively.
1.5 Limitations of Use
Epogen has not been shown to improve quality of life, fatigue, or patient well-being.
Epogen is not indicated for use:
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In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
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In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
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In patients scheduled for surgery who are willing to donate autologous blood.
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In patients undergoing cardiac or vascular surgery.
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As a substitute for RBC transfusions in patients who require immediate correction of anemia [see Clinical Pharmacology (12.2)].
2 DOSAGE AND ADMINISTRATION
2.1 eva luation of Iron Stores and Nutritional Factors
eva luate the iron status in all patients before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating Epogen [see Warnings and Precautions (5.11)].
2.2 Patients with Chronic Kidney Disease
In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL. No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks. Individualize dosing and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions [see Warnings and Precautions (5.1)]. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse events [see Boxed Warning and Clinical Studies (14)].
For all patients with CKD:
When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
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Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
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If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of Epogen by 25% or more as needed to reduce rapid responses.
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For patients who do not respond adequately, if the hemoglobin has not increased by more than 1 g/dL after 4 weeks of therapy, increase the dose by 25%.
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For patients who do not respond adequately over a 12-week escalation period, increasing the Epogen dose further is unlikely to improve response and may increase risks. Use the lowest dose that will maintain a hemoglobin level sufficient to reduce the need for RBC transfusions. eva luate other causes of anemia. Discontinue Epogen if responsiveness does not improve.
For patients with CKD on dialysis:
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Initiate Epogen treatment when the hemoglobin level is less than 10 g/dL.
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If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Epogen.
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The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. For pediatric patients, a starting dose of 50 Units/kg 3 times weekly intravenously or subcutaneously is recommended. The intravenous route is recommended for patients on hemodialysis.
For patients with CKD not on dialysis:
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Consider initiating Epogen treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
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The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
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Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
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If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of Epogen, and use the lowest dose of Epogen sufficient to reduce the need for RBC transfusions.
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The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.
When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions (5.1 and 5.3).
Refer patients who self-administer Epogen to the Instructions for Use [see Patient Counseling Information (17)].
2.3 Zidovudine-treated HIV-infected Patients
Starting Dose
The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.
Dose Adjustment
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If hemoglobin does not increase after 8 weeks of therapy, increase Epogen dose by approximately
50 to 100 Units/kg at 4- to 8-week intervals until hemoglobin reaches a level needed to avoid RBC transfusions or 300 Units/kg.
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Withhold Epogen if hemoglobin exceeds 12 g/dL. Resume therapy at a dose 25% below the previous dose when hemoglobin declines to less than 11 g/dL.
Discontinue Epogen if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
2.4 Patients on Cancer Chemotherapy
Initiate Epogen in patients on cancer chemotherapy only if the hemoglobin is less than 10 g/dL, and if there is a minimum of two additional months of planned chemotherapy.
Use the lowest dose of Epogen necessary to avoid RBC transfusions.
Recommended Starting Dose
Adults:
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150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or
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40,000 Units subcutaneously weekly until completion of a chemotherapy course.
Pediatric Patients (5 to 18 years):
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600 Units/kg intravenously weekly until completion of a chemotherapy course.
Dose Reduction
Reduce dose by 25% if:
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Hemoglobin increases greater than 1 g/dL in any 2-week period or
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Hemoglobin reaches a level needed to avoid RBC transfusion.
Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.
Dose Increase
After the initial 4 weeks of Epogen therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:
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300 Units/kg three times per week in adults or
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60,000 Units weekly in adults
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900 Units/kg (maximum 60,000 Units) weekly in children
After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue Epogen.
2.5 Surgery Patients
The recommended Epogen regimens are:
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300 Units/kg per day subcutaneously for 15 days total: administered daily for 10 days before surgery, on the day of surgery, and for 4 days after surgery.
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600 Units/kg subcutaneously in 4 doses administered 21, 14, and 7 days before surgery and on the day of surgery.
Deep venous thrombosis prophylaxis is recommended during Epogen therapy [see Warnings and Precautions (5.1)].
2.6 Preparation and Administration
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Do not shake. Do not use Epogen that has been shaken or frozen.
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Protect vials from light.
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Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use any vials exhibiting particulate matter or discoloration.
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Discard unused portions of Epogen in preservative-free vials. Do not re-enter preservative-free vials.
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Store unused portions of Epogen in multidose vials at 36°F to 46° F (2°C to 8°C). Discard 21 days after initial entry.
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Do not dilute. Do not mix with other drug solutions except for admixing as described below:
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Preservative-free Epogen from single-use vials may be admixed in a syringe with bacteriostatic 0.9% sodium chloride injection, USP, with benzyl alcohol 0.9% (bacteriostatic saline) in a 1:1 ratio using aseptic technique at the time of administration. Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and nursing mothers [see Use in Specific Populations (8.1, 8.3, 8.4)].
3 DOSAGE FORMS AND STRENGTHS
Single-dose vials: 2000, 3000, 4000, and 10,000 Units Epogen /1 mL
Multidose vials (contains benzyl alcohol): 20,000 Units Epogen /2 mL and 20,000 Units Epogen /1 mL
4 CONTRAINDICATIONS
Epogen is contraindicated in patients with:
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Uncontrolled hypertension [see Warnings and Precautions (5.4)]
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Pure red cell aplasia (PRCA) that begins after treatment with Epogen or other erythropoietin protein drugs [see Warnings and Precautions (5.7)]
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Serious allergic reactions to Epogen [see Warnings and Precautions (5.8)]
Epogen from multidose vials contains benzyl alcohol and is contraindicated in:
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Neonates, infants, pregnant women, and nursing mothers. Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. When therapy with Epogen is needed in neonates and infants, use single-dose vials; do not admix with bacteriostatic saline containing benzyl alcohol [see Use in Specific Populations (8.1, 8.3, 8.4)].
5 WARNINGS AND PRECAUTIONS
5.1 Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism
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In controlled clinical trials of patients with CKD comparing higher hemoglobin targets (13 - 14 g/dL) to lower targets (9 - 11.3 g/dL), Epogen and other ESAs increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups.
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Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit [see Clinical Studies (14.1)]. Use caution in patients with coexistent cardiovascular disease and stroke [see Dosage and Administration (2.2)]. Patients with CKD and an insufficient hemoglobin response to ESA therapy may be at even greater risk for cardiovascular reactions and mortality than other patients. A rate of hemoglobin rise of greater than 1 g/dL over 2 weeks may contribute to these risks.
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In controlled clinical trials of patients with cancer, Epogen and other ESAs increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke.
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In controlled clinical trials, ESAs increased the risk of death in patients undergoing coronary artery bypass graft surgery (CABG) and the risk of deep venous thrombosis (DVT) in patients undergoing orthopedic procedures.
The design and overall results of the 3 large trials comparing higher and lower hemoglobin targets are shown in Table 1.
Patients with Chronic Kidney Disease
Normal Hematocrit Study (NHS): A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR=1.27; 95% CI (1.04, 1.54); p=0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.
CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to epoetin alfa treatment targeting a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 of the 715 patients (18%) in the higher hemoglobin group compared to 97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; p = 0.03].
TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment (see Table 1), but the risk of stroke was increased |
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