Epoetin

Epoetin
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Vignesh Ponnusamy, M.B.B.S. [2]

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Black Box 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. ConditionName: 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. Use the lowest Epogen dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer: ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. Prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense Epogen to patients with cancer. Use the lowest dose to avoid RBC transfusions. Use ESAs only for anemia from myelosuppressive chemotherapy. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Discontinue following the completion of a chemotherapy course. Perisurgery: Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended.

Overview

Epoetin is a that is FDA approved for the {{{indicationType}}} of anemia due to chronic kidney disease, anemia due to zidovudine in hiv-infected patients, anemia due to chemotherapy in patients with cancer, reduction of allogeneic red blood cell transfusions in patients undergoing elective, noncardiac, nonvascular surgery.. There is a Black Box Warning for this drug as shown here. Common adverse reactions include .

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Evaluate 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

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.
• 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.
• Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
• 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.
• 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%.
• 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. Evaluate other causes of anemia. Discontinue Epogen if responsiveness does not improve.

For patients with CKD on dialysis

• Initiate Epogen treatment when the hemoglobin level is less than 10 g/dL.
• If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of Epogen.
• 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

• Consider initiating Epogen treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:
• The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and,
• Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
• 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.
• The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.

Zidovudine-treated 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.
• Starting Dose

• The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.

• Dose Adjustment

• 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.

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.

Patients on Cancer Chemotherapy

• 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.
• 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:

• 150 Units/kg subcutaneously 3 times per week until completion of a chemotherapy course or
• 40,000 Units subcutaneously weekly until completion of a chemotherapy course.

• Dose Reduction

• Reduce dose by 25% if:
• Hemoglobin increases greater than 1 g/dL in any 2-week period or
• 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:
• 300 Units/kg three times per week in adults or
• 60,000 Units weekly in adults
• 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.

Surgery Patients

• 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.
• 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.
• 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.

Preparation and Administration

• Do not shake. Do not use Epogen that has been shaken or frozen.
• Protect vials from light.
• 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.
• Discard unused portions of Epogen in preservative-free vials. Do not re-enter preservative-free vials.
• 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.
• Do not dilute. Do not mix with other drug solutions except for admixing as described below:
• 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.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Epoetin in adult patients.

Non–Guideline-Supported Use

Anemia - Congestive heart failure

• Subcutaneous erythropoietin (average dose: 5227 units/week) and intravenous (IV) iron (average dose: 185 milligrams (mg)/month).

Anemia due to radiation

• Epoetin alfa 200 units/kilogram/day for 5 consecutive days per week for up to 7 weeks during radiotherapy.

Anemia during the puerperium

• Intravenous (IV) erythropoietin (EPO) 300 units/kilogram/day plus IV iron sucrose 200 milligrams (mg)/day on days 1 to 4 postpartum.

Anemia - Hepatitis C, In patients being treated with a combination of ribavirin and interferon alfa or ribavirin and peginterferon alfa

• Epoetin alfa (Procrit(R)) 40,000 units subcutaneously once weekly.

Anemia - Multiple myeloma

• Erythropoietin (150 units/kilogram 3 times/week initially with adjustments every 3 weeks as needed).

Anemia - Myelodysplastic syndrome

• Erythropoietin alfa 150 international units/kilogram subcutaneously 3 times weekly for 26 weeks.

Anemia - Myelofibrosis

• Subcutaneous erythropoietin 10,000 units 3 days per week.

Anemia - Rheumatoid arthritis

• 100 units/kilogram (kg) 3 times per week for eight weeks.

Beta Thalassemia

• 150 international units/kilogram subcutaneously was administered 3 times per week for at least 12 weeks.

Blood unit collection for autotransfusion

• Epoetin alfa doses of 12,000 to 24,000 units subcutaneously once weekly or 300 to 600 units/kilogram twice weekly.

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Patients on Cancer Chemotherapy

• 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
• Pediatric Patients (5 to 18 years):

• 600 Units/kg intravenously weekly until completion of a chemotherapy course.

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Epoetin in pediatric patients.

Non–Guideline-Supported Use

Anemia of prematurity

• IV erythropoietin dosing was 1250 units/kg/wk as 5 divided doses.

Contraindications

• Uncontrolled hypertension.
• Pure red cell aplasia (PRCA) that begins after treatment with Epogen or other erythropoietin protein drugs.
• Serious allergic reactions to Epogen.
• Epogen from multidose vials contains benzyl alcohol and is contraindicated in:

• 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.

Warnings

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. ConditionName: 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. Use the lowest Epogen dose sufficient to reduce the need for red blood cell (RBC) transfusions. Cancer: ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers. Prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program to prescribe and/or dispense Epogen to patients with cancer. Use the lowest dose to avoid RBC transfusions. Use ESAs only for anemia from myelosuppressive chemotherapy. ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure. Discontinue following the completion of a chemotherapy course. Perisurgery: Due to increased risk of deep venous thrombosis (DVT), DVT prophylaxis is recommended.

Precautions

Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism

• 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.
• 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.
• 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.
• 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 nearly two-fold in the darbepoetin alfa -treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa- treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa -treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.

• Patients with Cancer

• An increased incidence of thromboembolic reactions, some serious and life-threatening, occurred in patients with cancer treated with ESAs.
• In a randomized, placebo-controlled study (Study 1 in Table 2 [see Warnings and Precautions (5.3)]) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).

• Patients Having Surgery

• An increased incidence of deep venous thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated [see Adverse Reactions (6.1)]. In a randomized, controlled study, 680 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, were randomized to 4 doses of 600 Units/kg epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment (n = 340) or to SOC treatment alone (n = 340). A higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%] patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients (n = 680) experienced 1 other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group). Deep venous thrombosis prophylaxis is strongly recommended when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients [see Dosage and Administration (2.5)].
• Increased mortality was observed in a randomized, placebo-controlled study of Epogen in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to Epogen versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all 4 deaths were associated with thrombotic events.

Prescribing and Distribution Program for Epogen in Patients With Cancer

• In order to prescribe and/or dispense Epogen to patients with cancer and anemia due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and comply with the ESA APPRISE Oncology Program requirements. To enroll, visit www.esa-apprise.com or call 1-866-284-8089 for further assistance. Additionally, prior to each new course of Epogen in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Epogen.

Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients With Cancer

• ESAs resulted in decreased locoregional control/progression-free survival and/or overall survival (see Table 2). These findings were observed in studies of patients with advanced head and neck cancer receiving radiation therapy (Studies 5 and 6), in patients receiving chemotherapy for metastatic breast cancer (Study 1) or lymphoid malignancy (Study 2), and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 7 and 8).

• Decreased Overall Survival

• Study 1 was described in the previous section [see Warnings and Precautions (5.1)]. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the 2 groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
• Study 2 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
• Study 7 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
• Study 8 was a randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).

• Decreased Progression-free Survival and Overall Survival

• Study 3 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse-free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.
• Study 4 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression-free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).
• Study 5 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms, respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).

Decreased Locoregional Control

• Study 6 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).

Hypertension

• Epogen is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of Epogen, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving Epogen.
• Appropriately control hypertension prior to initiation of and during treatment with Epogen. Reduce or withhold Epogen if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions.

Seizures

• Epogen increases the risk of seizures in patients with CKD. During the first several months following initiation of Epogen, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.

Lack or Loss of Hemoglobin Response to Epogen

• For lack or loss of hemoglobin response to Epogen, initiate a search for causative factors (e.g., iron deficiency, infection, inflammation, bleeding). If typical causes of lack or loss of hemoglobin response are excluded, evaluate for PRCA. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to Epogen therapy [see Dosage and Administration (2.2)].

Pure Red Cell Aplasia

• Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with Epogen. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which Epogen is not approved).
• If severe anemia and low reticulocyte count develop during treatment with Epogen, withhold Epogen and evaluate patients for neutralizing antibodies to erythropoietin. Contact Amgen (1-800-77-AMGEN) to perform assays for binding and neutralizing antibodies. Permanently discontinue Epogen in patients who develop PRCA following treatment with Epogen or other erythropoietin protein drugs. Do not switch patients to other ESAs.

Serious Allergic Reactions

• Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with Epogen. Immediately and permanently discontinue Epogen and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.

Albumin (Human)

• Epogen contains albumin, a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin.

Dialysis Management

• Patients may require adjustments in their dialysis prescriptions after initiation of Epogen. Patients receiving Epogen may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.

Laboratory Monitoring

• Evaluate transferrin saturation and serum ferritin prior to and during Epogen treatment. Administer supplemental iron therapy when serum ferritin is less than 100 mcg/L or when serum transferrin saturation is less than 20%. The majority of patients with CKD will require supplemental iron during the course of ESA therapy. Following initiation of therapy and after each dose adjustment, monitor hemoglobin weekly until the hemoglobin level is stable and sufficient to minimize the need for RBC transfusion.

• Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism
• Increased mortality and/or increased risk of tumor progression or recurrence in Patients With Cancer
• Hypertension
• Seizures
• PRCA
• Serious allergic reactions

Adverse Reactions

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice.

Patients with Chronic Kidney Disease

• Adult Patients

• Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to Epogen. In these studies, the mean age of patients was 48 years (range: 20 to 80 years). One hundred and thirty-three (55%) patients were men. The racial distribution was as follows: 177 (73%) patients were white, 48 (20%) patients were black, 4 (2%) patients were Asian, 12 (5%) patients were other, and racial information was missing for 3 (1%) patients.
• Two double-blind, placebo-controlled studies, including 210 patients with CKD not on dialysis, were used to identify the adverse reactions to Epogen. In these studies, the mean age of patients was 57 years (range: 24 to 79 years). One hundred and twenty-one (58%) patients were men. The racial distribution was as follows: 164 (78%) patients were white, 38 (18%) patients were black, 3 (1%) patients were Asian, 3 (1%) patients were other, and racial information was missing for 2 (1%) patients.
• The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

• An additional serious adverse reaction that occurred in less than 5% of epoetin alfa-treated dialysis patients and greater than placebo was thrombosis (2.7% Epogen and 1% placebo) [see Warnings and Precautions (5.1)].
• The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:

• Additional serious adverse reactions that occurred in less than 5% of epoetin alfa-treated patients not on dialysis and greater than placebo were erythema (0.8% Epogen and 0% placebo) and myocardial infarction (0.8% Epogen and 0% placebo) [see Warnings and Precautions (5.1)].
• Pediatric Patients

• In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.

Zidovudine-treated HIV-infected Patients

• A total of 297 zidovudine-treated HIV-infected patients were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive Epogen and 153 (52%) patients were randomly assigned to receive placebo. Epogen was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.
• For the combined Epogen treatment groups, a total of 141 (98%) men and 3 (2%) women between the ages of 24 and 64 years were enrolled. The racial distribution of the combined Epogen treatment groups was as follows: 129 (90%) white, 8 (6%) black, 1 (1%) Asian, and 6 (4%) other.
• In double-blind, placebo-controlled studies of 3 months duration involving approximately 300 zidovudine-treated HIV-infected patients, adverse reactions with an incidence of ≥ 1% in patients treated with Epogen were:

Cancer Patients on Chemotherapy

• The data below were obtained in Study C1, a 16-week, double-blind, placebo-controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to Epogen received at least 1 dose of study drug, and 165 of 170 patients (97%) randomized to placebo received at least 1 placebo dose. For the once weekly Epogen-treatment group, a total of 76 men (45%) and 92 women (55%) between the ages of 20 and 88 years were treated. The racial distribution of the Epogen-treatment group was 158 white (94%) and 10 black (6%). Epogen was administered once weekly for an average of 13 weeks at a dose of 20,000 to 60,000 IU subcutaneously (mean weekly dose was 49,000 IU).
• The adverse reactions with a reported incidence of ≥ 5% in Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Surgery Patients

• Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive Epogen and 103 (22%) patients were randomly assigned to receive placebo. Epogen was administered daily at a dose of 100 to 300 IU/kg subcutaneously for 15 days or at 600 IU/kg once weekly for 4 weeks.
• For the combined Epogen treatment groups, a total of 90 (25%) and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined Epogen treatment groups was as follows: 288 (80%) white, 64 (18%) black, 1 (< 1%) Asian, and 5 (1%) other.
• The adverse reactions with a reported incidence of ≥ 1% in Epogen-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:

Postmarketing Experience

• Because postmarketing reporting of adverse reactions is voluntary and from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
• The following adverse reactions have been identified during postmarketing use of Epogen:

• Seizures
• PRCA
• Serious allergic reactions
• Injection site reactions, including irritation and pain
• Porphyria

Drug Interactions

• No formal drug interaction studies have been conducted with Epogen.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category C

• There are no adequate and well-controlled studies of Epogen use during pregnancy. There are limited data on Epogen use in pregnant women. In animal reproductive and developmental toxicity studies, adverse fetal effects occurred when pregnant rats received epoetin alfa at doses approximating the clinical recommended starting doses. Single-dose formulations of Epogen should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
• There are reports of at least 33 pregnant women with anemia alone or anemia associated with severe renal disease and other hematologic disorders who received Epogen. Polyhydramnios and intrauterine growth restriction were reported in women with chronic renal disease, which is associated with an increased risk for these adverse pregnancy outcomes. There was 1 infant born with pectus excavatum and hypospadias following exposure during the first trimester. Due to the limited number of exposed pregnancies and multiple confounding factors (such as underlying maternal conditions, other maternal medications, and gestational timing of exposure), these published case reports and studies do not reliably estimate the frequency or absence of adverse outcomes.
• When healthy rats received Epogen at doses of 100 Units/kg/day during mating and through early pregnancy (dosing stopped prior to organogenesis), there were slight increases in the incidences of pre-and post-implantation loss, and a decrease in live fetuses. This animal dose level of 100 Units/kg/day may approximate the clinical recommended starting dose, depending on the treatment indication. When healthy pregnant rats and rabbits received intravenous doses of up to 500 mg/kg/day of Epogen only during organogenesis, no teratogenic effects were observed in the offspring.

When healthy pregnant rats received Epogen at doses of 500 Units/kg/day late in pregnancy (after the period of organogenesis), offspring had decreased number of caudal vertebrae and growth delays.

• Women who become pregnant during Epogen treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Epoetin in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Epoetin during labor and delivery.

Nursing Mothers

• The multidose vials of Epogen are formulated with benzyl alcohol. Do not administer Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to a nursing woman. When therapy with Epogen is needed in nursing women, use a benzyl alcohol-free formulation [see Dosage and Administration (2) and Contraindications (4)].
• It is not known whether Epogen is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when Epogen from single-dose vials is administered to a nursing woman.

Pediatric Use

• The multidose vials are formulated with benzyl alcohol. Do not administer Epogen from multidose vials, or Epogen from single-dose vials admixed with bacteriostatic saline containing benzyl alcohol, to neonates or infants. When therapy with Epogen is needed in neonates and infants, use a benzyl alcohol-free formulation.
• Benzyl alcohol has been associated with serious adverse events and death, particularly in pediatric patients. The "gasping syndrome," (characterized by central nervous system depression, metabolic acidosis, gasping respirations, and high levels of benzyl alcohol and its metabolites found in the blood and urine) has been associated with benzyl alcohol dosages > 99 mg/kg/day in neonates and low-birthweight neonates. Additional symptoms may include gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse.
• Although normal therapeutic doses of this product deliver amounts of benzyl alcohol that are substantially lower than those reported in association with the "gasping syndrome", the minimum amount of benzyl alcohol at which toxicity may occur is not known. Premature and low-birthweight infants, as well as patients receiving high dosages, may be more likely to develop toxicity. Practitioners administering this and other medications containing benzyl alcohol should consider the combined daily metabolic load of benzyl alcohol from all sources.
• Pediatric Patients on Dialysis

• Epogen is indicated in pediatric patients, ages 1 month to 16 years of age, for the treatment of anemia associated with CKD requiring dialysis. Safety and effectiveness in pediatric patients less than 1 month old have not been established.

The safety data from these studies are similar to those obtained from the studies of Epogen in adult patients with CKD.

• Pediatric Cancer Patients on Chemotherapy

• Epogen is indicated in patients 5 to 18 years old for the treatment of anemia due to concomitant myelosuppressive chemotherapy. Safety and effectiveness in pediatric patients less than 5 years of age have not been established. The safety data from these studies are similar to those obtained from the studies of Epogen in adult patients with cancer.

• Pediatric Patients With HIV Infection Receiving Zidovudine

• Published literature has reported the use of Epogen in 20 zidovudine-treated, anemic, pediatric patients with HIV infection, ages 8 months to 17 years, treated with 50 to 400 Units/kg subcutaneously or intravenously 2 to 3 times per week. Increases in hemoglobin levels and in reticulocyte counts and decreases in or elimination of RBC transfusions were observed.

• Pharmacokinetics in Neonates

• Limited pharmacokinetic data from a study of 7 preterm, very low birth weight neonates and 10 healthy adults given intravenous erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.

Geriatic Use

• Of the 4553 patients who received Epogen in the 6 studies for treatment of anemia due to CKD not receiving dialysis, 2726 (60%) were age 65 years and over, while 1418 (31%) were 75 years and over. Of the 757 patients who received Epogen in the 3 studies of CKD patients on dialysis, 361 (47%) were age 65 years and over, while 100 (13%) were 75 years and over. No differences in safety or effectiveness were observed between geriatric and younger patients. Dose selection and adjustment for an elderly patient should be individualized to achieve and maintain the target hemoglobin [see Dosage and Administration (2)].
• Among 778 patients enrolled in the 3 clinical studies of Epogen for the treatment of anemia due to concomitant chemotherapy, 419 received Epogen and 359 received placebo. Of the 419 who received Epogen, 247 (59%) were age 65 years and over, while 78 (19%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epogen in geriatric and younger patients within the 3 studies were similar.
• Among 1731 patients enrolled in the 6 clinical studies of Epogen for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received Epogen and 646 received placebo or standard of care treatment. Of the 1085 patients who received Epogen, 582 (54%) were age 65 years and over, while 245 (23%) were 75 years and over. No overall differences in safety or effectiveness were observed between geriatric and younger patients. The dose requirements for Epogen in geriatric and younger patients within the 4 studies using the 3 times weekly schedule and 2 studies using the weekly schedule were similar.
• Insufficient numbers of patients age 65 years or older were enrolled in clinical studies of Epogen for the treatment of zidovudine in HIV-infected patients to determine whether they respond differently from younger patients.

Gender

There is no FDA guidance on the use of Epoetin with respect to specific gender populations.

Race

There is no FDA guidance on the use of Epoetin with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Epoetin in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Epoetin in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Epoetin in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Epoetin in patients who are immunocompromised.

Administration and Monitoring

Administration

• Subcutaneous

• Intravenous

Monitoring

• To undergo regular blood pressure monitoring.
• Evaluate transferrin saturation and serum ferritin prior to and during Epogen treatment.

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

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Epoetin in the drug label.

Overdosage

• Epogen overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of Epogen dosage and/or with phlebotomy as clinically indicated.
• Cases of severe hypertension have been observed following overdose with ESAs

Chronic Overdose

There is limited information regarding Chronic Overdose of Epoetin in the drug label.

Pharmacology

There is limited information regarding Epoetin Pharmacology in the drug label.

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Epoetin in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Epoetin in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Epoetin in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Epoetin in the drug label.

How Supplied

Storage

There is limited information regarding Epoetin Storage in the drug label.

Images

Drug Images

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Package and Label Display Panel

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Patient Counseling Information

There is limited information regarding Patient Counseling Information of Epoetin in the drug label.

Precautions with Alcohol

• Alcohol-Epoetin interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.

Brand Names

• ®

Look-Alike Drug Names

• A® — B®

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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