Retacrit

RETACRIT is an erythropoiesis-stimulating agent (ESA) indicated for:

• •Treatment of anemia due to
  • oChronic Kidney Disease (CKD) in patients on dialysis and not on dialysis (
    1.1 Anemia Due to Chronic Kidney Disease

    RETACRIT 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.
    ).
  • oZidovudine in patients with Human Immunodeficiency Virus (HIV) infection (
    1.2 Anemia Due to Zidovudine in Patients with HIV Infection

    RETACRIT is indicated for the treatment of anemia due to zidovudine administered at ≤ 4,200 mg/week in patients with HIV infection with endogenous serum erythropoietin levels of ≤ 500 mUnits/mL.
    ).
  • oThe effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy (
    1.3 Anemia Due to Chemotherapy in Patients with Cancer

    RETACRIT 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.
    ).
• •Reduction of allogeneic red blood cell (RBC) transfusions in patients undergoing elective, noncardiac, nonvascular surgery (
  1.4 Reduction of Allogeneic Red Blood Cell Transfusions in Patients Undergoing Elective, Noncardiac, Nonvascular Surgery

  RETACRIT 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. RETACRIT is not indicated for patients who are willing to donate autologous blood pre-operatively.
  ).

RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being (

RETACRIT is not indicated for use:

• •In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy (
  1.5 Limitations of Use

  RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being.

  RETACRIT is not indicated for use:

  • •In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • •In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • •In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
  • •In patients scheduled for surgery who are willing to donate autologous blood.
  • •In patients undergoing cardiac or vascular surgery.
  • •As a substitute for RBC transfusions in patients who require immediate correction of anemia.
  ).
• •In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure (
  1.5 Limitations of Use

  RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being.

  RETACRIT is not indicated for use:

  • •In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • •In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • •In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
  • •In patients scheduled for surgery who are willing to donate autologous blood.
  • •In patients undergoing cardiac or vascular surgery.
  • •As a substitute for RBC transfusions in patients who require immediate correction of anemia.
  ).
• •In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion (
  1.5 Limitations of Use

  RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being.

  RETACRIT is not indicated for use:

  • •In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • •In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • •In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
  • •In patients scheduled for surgery who are willing to donate autologous blood.
  • •In patients undergoing cardiac or vascular surgery.
  • •As a substitute for RBC transfusions in patients who require immediate correction of anemia.
  ).
• •In patients scheduled for surgery who are willing to donate autologous blood (
  1.5 Limitations of Use

  RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being.

  RETACRIT is not indicated for use:

  • •In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • •In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • •In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
  • •In patients scheduled for surgery who are willing to donate autologous blood.
  • •In patients undergoing cardiac or vascular surgery.
  • •As a substitute for RBC transfusions in patients who require immediate correction of anemia.
  ).
• •In patients undergoing cardiac or vascular surgery (
  1.5 Limitations of Use

  RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being.

  RETACRIT is not indicated for use:

  • •In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • •In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • •In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
  • •In patients scheduled for surgery who are willing to donate autologous blood.
  • •In patients undergoing cardiac or vascular surgery.
  • •As a substitute for RBC transfusions in patients who require immediate correction of anemia.
  ).
• •As a substitute for RBC transfusions in patients who require immediate correction of anemia (
  1.5 Limitations of Use

  RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being.

  RETACRIT is not indicated for use:

  • •In patients with cancer receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy.
  • •In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure.
  • •In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion.
  • •In patients scheduled for surgery who are willing to donate autologous blood.
  • •In patients undergoing cardiac or vascular surgery.
  • •As a substitute for RBC transfusions in patients who require immediate correction of anemia.
  ).

• •Evaluate iron status before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia before initiating treatment (
  2.1 Important Dosing Information

  Evaluation of Iron Stores and Nutritional Factors

  Evaluate the iron status in all patients before and during 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.

  Monitoring of Response to Therapy

  Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating RETACRIT. 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.

  Selection of Formulation

  In pregnant women, lactating women, neonates, and infants use only single-dose vials (the benzyl alcohol-free formulation)

  [see Contraindications (4)and Use in Specific Populations (8.1, 8.2, and 8.4)]

  .
  ).
• •In pregnant women, lactating women, neonates, infants: Use only single-dose vials (
  2.1 Important Dosing Information

  Evaluation of Iron Stores and Nutritional Factors

  Evaluate the iron status in all patients before and during 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.

  Monitoring of Response to Therapy

  Correct or exclude other causes of anemia (e.g., vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) before initiating RETACRIT. 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.

  Selection of Formulation

  In pregnant women, lactating women, neonates, and infants use only single-dose vials (the benzyl alcohol-free formulation)

  [see Contraindications (4)and Use in Specific Populations (8.1, 8.2, and 8.4)]

  .
  ).
• •Patients with CKD: Initial dose: 50 to 100 Units/kg 3 times weekly (adults) and 50 Units/kg 3 times weekly (pediatric patients). Individualize maintenance dose. Intravenous route recommended for patients on hemodialysis (
  2.2 Patients with Chronic Kidney Disease

  In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered 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 RETACRIT 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 reactions

  [see Boxed Warningand 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 RETACRIT 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 RETACRIT 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 RETACRIT if responsiveness does not improve.

  For adult patients with CKD on dialysis:

  • •Initiate RETACRIT 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 RETACRIT.
  • •The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously. The intravenous route is recommended for patients on hemodialysis.

  For adult patients with CKD not on dialysis:

  • •Consider initiating RETACRIT treatment only when the hemoglobin level is less than 10 g/dL
    and
    the following considerations apply:
    • oThe rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion
      
      
      and,
    • oReducing 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 RETACRIT, and use the lowest dose of RETACRIT 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.

  For pediatric patients with CKD:

  • •Initiate RETACRIT treatment only when the hemoglobin level is less than 10 g/dL.
  • •If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of RETACRIT.
  • •The recommended starting dose for pediatric patients (ages 1 month or older) is 50 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 5.2).
  ).
• •Patients on Zidovudine due to HIV infection: 100 Units/kg 3 times weekly (
  2.3 Zidovudine-treated Patients with HIV Infection

  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 RETACRIT 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 RETACRIT 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 RETACRIT if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
  ).
• •Patients with Cancer on Chemotherapy: 40,000 Units weekly or 150 Units/kg 3 times weekly (adults); 600 Units/kg intravenously weekly (pediatric patients ≥ 5 years) (
  2.4 Patients on Cancer Chemotherapy

  Initiate RETACRIT 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 RETACRIT 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.

  Pediatric Patients (5 to 18 years):

  • •600 Units/kg intravenously 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 RETACRIT 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 pediatric patients

  After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue RETACRIT.
  ).
• •Surgery Patients: 300 Units/kg per day daily for 15 days or 600 Units/kg weekly (
  2.5 Surgery Patients

  The recommended RETACRIT regimens are:

  • •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 RETACRIT therapy

  [see Warnings and Precautions (5.1)]

  .
  ).

Injection

• •2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, 10,000 Units/mL, and 40,000 Units/mL in single-dose vials (
  3 DOSAGE FORMS AND STRENGTHS

  Injection

  • •2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, 10,000 Units/mL, and 40,000 Units/mL in single-dose vials .
  • •20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL in multiple-dose vials containing benzyl alcohol .

  Injection:

  • •2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, 10,000 Units/mL, and 40,000 Units/mL of RETACRIT as a clear and colorless liquid in single-dose vials.
  • •20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL of RETACRIT as a clear and colorless liquid in multiple-dose vials (contains benzyl alcohol).
  ).
• •20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL in multiple-dose vials containing benzyl alcohol (
  3 DOSAGE FORMS AND STRENGTHS

  Injection

  • •2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, 10,000 Units/mL, and 40,000 Units/mL in single-dose vials .
  • •20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL in multiple-dose vials containing benzyl alcohol .

  Injection:

  • •2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, 10,000 Units/mL, and 40,000 Units/mL of RETACRIT as a clear and colorless liquid in single-dose vials.
  • •20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL of RETACRIT as a clear and colorless liquid in multiple-dose vials (contains benzyl alcohol).
  ).

RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated in pregnant women

The limited available data on epoetin alfa use in pregnant women are insufficient to determine a drug-associated risk of adverse developmental outcomes. In animal reproductive and developmental toxicity studies, adverse fetal effects including embryo-fetal death, skeletal anomalies, and growth defects occurred when pregnant rats received epoetin alfa at doses approximating the clinical recommended starting doses

The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

• •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 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), epoetin alfa 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, epoetin alfa 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.

  Table 1. Randomized Controlled Trials Showing Adverse Cardiovascular Outcomes in Patients with CKD

  	Normal Hematocrit Study (NHS) (N = 1265)	CHOIR (N = 1432)	TREAT (N = 4038)
  Time Period of Trial	1993 to 1996	2003 to 2006	2004 to 2009
  Population	CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa	CKD patients not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa	CKD patients not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL
  Hemoglobin Target; Higher vs. Lower (g/dL)	14.0 vs. 10.0	13.5 vs. 11.3	13.0 vs. ≥ 9.0
  Median (Q1, Q3) Achieved Hemoglobin level (g/dL)	12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7)	13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6)	12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3)
  Primary Endpoint	All-cause mortality or non-fatal MI	All-cause mortality, MI, hospitalization for CHF, or stroke	All-cause mortality, MI, myocardial ischemia, heart failure, and stroke
  Hazard Ratio or Relative Risk (95% CI)	1.28 (1.06 – 1.56)	1.34 (1.03 – 1.74)	1.05 (0.94 – 1.17)
  Adverse Outcome for Higher Target Group	All-cause mortality	All-cause mortality	Stroke
  Hazard Ratio or Relative Risk (95% CI)	1.27 (1.04 – 1.54)	1.48 (0.97 – 2.27)	1.92 (1.38 – 2.68)

  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 2 in Table 2

  [see Warnings and Precautions (5.2)]

  ) 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 epoetin alfa in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to epoetin alfa 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.
  and
  14.1 Patients with Chronic Kidney Disease

  Adult Patients on Dialysis

  Patients with chronic kidney disease on dialysis: ESA effects on rates of transfusion

  In clinical studies of patients with CKD on dialysis, epoetin alfa increased hemoglobin levels and decreased the need for RBC transfusion. Overall, more than 95% of patients were RBC transfusion-independent after receiving epoetin alfa for 3 months. In clinical studies at starting doses of 50 to 150 Units/kg 3 times weekly, adult patients responded with an average rate of hemoglobin rise as presented in Table 8.

  Table 8. Average Rate of Hemoglobin Rise in 2 Weeks

  Starting Dose (3 Times Weekly Intravenously)	Hemoglobin Increase in 2 Weeks
  50 Units/kg	0.5 g/dL
  100 Units/kg	0.8 g/dL
  150 Units/kg	1.2 g/dL

  The safety and efficacy of epoetin alfa were evaluated in 13 clinical studies involving intravenous administration to a total of 1010 patients on dialysis with anemia. Overall, more than 90% of the patients treated with epoetin alfa experienced improvement in hemoglobin concentrations. In the 3 largest of these clinical studies, the median maintenance dose necessary to maintain the hemoglobin between 10 to 12 g/dL was approximately 75 Units/kg 3 times weekly. More than 95% of patients were able to avoid RBC transfusions. In the largest US multicenter study, approximately 65% of the patients received doses of 100 Units/kg 3 times weekly or less to maintain their hemoglobin at approximately 11.7 g/dL. Almost 10% of patients received a dose of 25 Units/kg or less, and approximately 10% received a dose of more than 200 Units/kg 3 times weekly to maintain their hemoglobin at this level.

  In the Normal Hematocrit Study, the yearly transfusion rate was 51.5% in the lower hemoglobin group (10 g/dL) and 32.4% in the higher hemoglobin group (14 g/dL).

  Other ESA trials

  In a 26-week, double-blind, placebo-controlled study, 118 patients on dialysis with an average hemoglobin of approximately 7 g/dL were randomized to either epoetin alfa or placebo. By the end of the study, average hemoglobin increased to approximately 11 g/dL in the epoetin alfa-treated patients and remained unchanged in patients receiving placebo. Epoetin alfa-treated patients experienced improvements in exercise tolerance and patient-reported physical functioning at month 2 that were maintained throughout the study.

  A multicenter, unit-dose study was also conducted in 119 patients receiving peritoneal dialysis who self-administered epoetin alfa subcutaneously. Patients responded to epoetin alfa administered subcutaneously in a manner similar to patients receiving intravenous administration.

  Pediatric Patients with CKD on Dialysis

  The safety and efficacy of epoetin alfa were studied in a placebo-controlled, randomized study of 113 pediatric patients with anemia (hemoglobin ≤ 9 g/dL) undergoing peritoneal dialysis or hemodialysis. The initial dose of epoetin alfa was 50 Units/kg intravenously or subcutaneously 3 times weekly. The dose of study drug was titrated to achieve either a hemoglobin of 10 to 12 g/dL or an absolute increase in hemoglobin of 2 g/dL over baseline.

  At the end of the initial 12 weeks, a statistically significant rise in mean hemoglobin (3.1 g/dL vs. 0.3 g/dL) was observed only in the epoetin alfa arm. The proportion of pediatric patients achieving a hemoglobin of 10 g/dL, or an increase in hemoglobin of 2 g/dL over baseline, at any time during the first 12 weeks was higher in the epoetin alfa arm (96% vs. 58%). Within 12 weeks of initiating epoetin alfa therapy, 92.3% of the pediatric patients were RBC transfusion independent as compared to 65.4% who received placebo. Among patients who received 36 weeks of epoetin alfa, hemodialysis patients received a higher median maintenance dose [167 Units/kg/week (n = 28) vs. 76 Units/kg/week (n = 36)] and took longer to achieve a hemoglobin of 10 to 12 g/dL (median time to response 69 days vs. 32 days) than patients undergoing peritoneal dialysis.

  Adult Patients with CKD Not Requiring Dialysis

  Four clinical studies were conducted in patients with CKD not on dialysis involving 181 patients treated with epoetin alfa. These patients responded to epoetin alfa therapy in a manner similar to that observed in patients on dialysis. Patients with CKD not on dialysis demonstrated a dose-dependent and sustained increase in hemoglobin when epoetin alfa was administered by either an intravenous or subcutaneous route, with similar rates of rise of hemoglobin when epoetin alfa was administered by either route.

  Patients with chronic kidney disease not on dialysis: ESA effects on rates of transfusion

  In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered an ESA to target a hemoglobin of 13 g/dL compared to the control arm in which an ESA was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of epoetin alfa to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile

  [see Warnings and Precautions (5.1)]

  .

  ESA Effects on rates of death and other serious cardiac adverse reactions

  Three randomized outcome trials (Normal Hematocrit Study [NHS], Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease [CHOIR], and Trial of Darbepoetin Alfa in Type 2 Diabetes and CKD [TREAT]) have been conducted in patients with CKD using epoetin alfa/darbepoetin alfa to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile

  [see Warnings and Precautions (5.1)]

  .
  ). Use caution in patients with coexistent cardiovascular disease and stroke (
  5.1 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), epoetin alfa 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, epoetin alfa 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.

  Table 1. Randomized Controlled Trials Showing Adverse Cardiovascular Outcomes in Patients with CKD

  	Normal Hematocrit Study (NHS) (N = 1265)	CHOIR (N = 1432)	TREAT (N = 4038)
  Time Period of Trial	1993 to 1996	2003 to 2006	2004 to 2009
  Population	CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa	CKD patients not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa	CKD patients not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL
  Hemoglobin Target; Higher vs. Lower (g/dL)	14.0 vs. 10.0	13.5 vs. 11.3	13.0 vs. ≥ 9.0
  Median (Q1, Q3) Achieved Hemoglobin level (g/dL)	12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7)	13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6)	12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3)
  Primary Endpoint	All-cause mortality or non-fatal MI	All-cause mortality, MI, hospitalization for CHF, or stroke	All-cause mortality, MI, myocardial ischemia, heart failure, and stroke
  Hazard Ratio or Relative Risk (95% CI)	1.28 (1.06 – 1.56)	1.34 (1.03 – 1.74)	1.05 (0.94 – 1.17)
  Adverse Outcome for Higher Target Group	All-cause mortality	All-cause mortality	Stroke
  Hazard Ratio or Relative Risk (95% CI)	1.27 (1.04 – 1.54)	1.48 (0.97 – 2.27)	1.92 (1.38 – 2.68)

  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 2 in Table 2

  [see Warnings and Precautions (5.2)]

  ) 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 epoetin alfa in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to epoetin alfa 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.
  ).
• •Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer (
  5.2 Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer

  ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS) (see Table 2).

  Adverse effects on PFS and/or OS were observed in studies of patients receiving chemotherapy for breast cancer (Studies 1, 2, and 4), lymphoid malignancy (Study 3), and cervical cancer (Study 5); in patients with advanced head and neck cancer receiving radiation therapy (Studies 6 and 7); and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 8 and 9).

  Table 2. Randomized, Controlled Studies with Decreased Survival and/or Decreased Locoregional Control

  Study/Tumor/(n)	Hemoglobin Target	Achieved Hemoglobin (Median; Q1, Q3 Q1 = 25thpercentile; Q3 = 75thpercentile )	Primary Efficacy Outcome	Adverse Outcome for ESA-containing Arm
  Chemotherapy
  Study 1 Metastatic breast cancer (n = 2098)	≤12 g/dLThis study did not include a defined hemoglobin target. Doses were titrated to achieve and maintain the lowest hemoglobin level sufficient to avoid transfusion and not to exceed 12 g/dL.	11.6 g/dL; 10.7, 12.1 g/dL	Progression-free survival (PFS)	Decreased progression-free and overall survival
  Study 2 Metastatic breast cancer (n = 939)	12–14 g/dL	12.9 g/dL; 12.2, 13.3 g/dL	12-month overall survival	Decreased 12-month survival
  Study 3 Lymphoid malignancy (n = 344)	13–15 g/dL (M) 13–14 g/dL (F)	11 g/dL; 9.8, 12.1 g/dL	Proportion of patients achieving a hemoglobin response	Decreased overall survival
  Study 4 Early breast cancer (n = 733)	12.5–13 g/dL	13.1 g/dL; 12.5, 13.7 g/dL	Relapse-free and overall survival	Decreased 3-year relapse-free and overall survival
  Study 5 Cervical cancer (n = 114)	12–14 g/dL	12.7 g/dL; 12.1, 13.3 g/dL	Progression-free and overall survival and locoregional control	Decreased 3-year progression-free and overall survival and locoregional control
  Radiotherapy Alone
  Study 6 Head and neck cancer (n = 351)	≥ 15 g/dL (M) ≥ 14 g/dL (F)	Not available	Locoregional progression-free survival	Decreased 5-year locoregional progression-free and overall survival
  Study 7 Head and neck cancer (n = 522)	14–15.5 g/dL	Not available	Locoregional disease control	Decreased locoregional disease control
  No Chemotherapy or Radiotherapy
  Study 8 Non-small cell lung cancer (n = 70)	12–14 g/dL	Not available	Quality of life	Decreased overall survival
  Study 9 Non-myeloid malignancy (n = 989)	12–13 g/dL	10.6 g/dL; 9.4, 11.8 g/dL	RBC transfusions	Decreased overall survival

  Decreased Overall Survival

  Study 2 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 3 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 8 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 9 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 1 was a randomized, open-label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non-inferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. At the time of clinical data cutoff, the median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. There were more deaths from disease progression in the epoetin alfa plus SOC arm (59% vs. 56%) and more thrombotic vascular events in the epoetin alfa plus SOC arm (3% vs. 1%). At the final analysis, 1653 deaths were reported (79.8% subjects in the epoetin alfa plus SOC group and 77.8% subjects in the SOC group). Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07, 95% CI: 0.97, 1.18).

  Study 4 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 5 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 6 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 7 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 to 15.5 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: Control hypertension prior to initiating and during treatment with RETACRIT (
  5.3 Hypertension

  RETACRIT is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of epoetin alfa, 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 epoetin alfa.

  Appropriately control hypertension prior to initiation of and during treatment with RETACRIT. Reduce or withhold RETACRIT if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions

  [see Patient Counseling Information (17)]

  .
  ).
• •Seizures: Epoetin alfa products increase the risk for seizures in patients with CKD (
  5.4 Seizures

  Epoetin alfa products, including RETACRIT, increase the risk of seizures in patients with CKD. During the first several months following initiation of RETACRIT, 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.
  ). Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms (
  5.4 Seizures

  Epoetin alfa products, including RETACRIT, increase the risk of seizures in patients with CKD. During the first several months following initiation of RETACRIT, 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.
  ).
• •PRCA: If severe anemia and low reticulocyte count develop during RETACRIT treatment, withhold RETACRIT and evaluate for PRCA (
  5.6 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 epoetin alfa. 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 RETACRIT is not approved).

  If severe anemia and low reticulocyte count develop during treatment with RETACRIT, withhold RETACRIT and evaluate patients for neutralizing antibodies to erythropoietin. Contact Hospira, Inc., a Pfizer Company (1-800-438-1985) to perform assays for binding and neutralizing antibodies. Permanently discontinue RETACRIT in patients who develop PRCA following treatment with RETACRIT or other erythropoietin protein drugs. Do not switch patients to other ESAs.
  ).
• •Serious Allergic Reactions: Discontinue RETACRIT and manage reactions (
  5.7 Serious Allergic Reactions

  Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with epoetin alfa products. Immediately and permanently discontinue RETACRIT and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.
  ).
• •Severe Cutaneous Reactions: Discontinue RETACRIT (
  5.8 Severe Cutaneous Reactions

  Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including epoetin alfa) in the postmarketing setting. Discontinue RETACRIT therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.
  ).
• •Phenylketonurics: Contains phenylalanine (
  5.10 Risk in Patients with Phenylketonuria

  Phenylalanine can be harmful to patients with phenylketonuria (PKU). RETACRIT contains phenylalanine, a component of aspartame. Each 1 mL single-dose vial of 2,000, 3,000, 4,000, 10,000, and 40,000 Units of epoetin alfa-epbx injection contains 0.5 mg of phenylalanine. Before prescribing RETACRIT to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including RETACRIT.
  ).