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RETACRIT™
(epoetin alfa-epbx) Injection for Intravenous or Subcutaneous Use
WARNING
ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE
Epoetin alfa-epbx is a 165-amino acid erythropoiesis-stimulating glycoprotein manufactured by recombinant DNA technology. It has a molecular weight of approximately 30,400 daltons and is produced in Chinese Hamster Ovary (CHO) cell line. The product contains the identical amino acid sequence of isolated natural erythropoietin.
RETACRIT (epoetin alfa-epbx) injection for intravenous or subcutaneous administration is a sterile, clear, colorless solution in single-dose vials, formulated with an isotonic sodium chloride/sodium phosphatebuffered solution.
Each 1 mL single-dose vial of 2,000, 3,000, 4,000, and 10,000 Units of epoetin alfa-epbx contains calcium chloride dihydrate (0.01 mg), glycine (7.5 mg), isoleucine (1 mg), leucine (1 mg), L-glutamic acid (0.25 mg), phenylalanine (0.5 mg), polysorbate 20 (0.1 mg), sodium chloride (2.4 mg), sodium phosphate dibasic anhydrous (4.9 mg), sodium phosphate monobasic monohydrate (1.3 mg), and threonine (0.25 mg), in Water for Injection, USP.
Each 1 mL vial of 40,000 Units of epoetin alfa-epbx contains calcium chloride dihydrate (0.01 mg), glycine (7.5 mg), isoleucine (1 mg), leucine (1 mg), L-glutamic acid (0.25 mg), phenylalanine (0.5 mg), polysorbate 20 (0.1 mg), sodium chloride (2.2 mg), sodium phosphate dibasic anhydrous (5.7 mg), sodium phosphate monobasic monohydrate (1.5 mg), and threonine (0.25 mg), in Water for Injection, USP.
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.
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.
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.
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:
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.
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.
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 RETACRIT sufficient to reduce the need for RBC transfusions [see WARNINGS AND PRECAUTIONS]. Physicians and patients should weigh the possible benefits of decreasing transfusions against the increased risks of death and other serious cardiovascular adverse reactions [see BOX WARNING and Clinical Studies].
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.
When treating patients who have chronic kidney disease and cancer, physicians should refer to Warnings and Precautions (5.1 and 5.2).
The recommended starting dose in adults is 100 Units/kg as an intravenous or subcutaneous injection 3 times per week.
Discontinue RETACRIT if an increase in hemoglobin is not achieved at a dose of 300 Units/kg for 8 weeks.
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.
Adults:
Pediatric Patients (5 To 18 Years):
Reduce dose by 25% if:
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.
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:
After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue RETACRIT.
The recommended RETACRIT regimens are:
Deep venous thrombosis prophylaxis is recommended during RETACRIT therapy [see WARNINGS AND PRECAUTIONS].
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.
RETACRIT (epoetin alfa-epbx) injection is a sterile, preservative-free, clear, and colorless solution in single-dose vials available as:
| Unit of Sale | Strength | Each Single Unit of Use |
| NDC 0069-1305-10 Carton containing 10 vials |
2,000 Units/mL | NDC 0069-1305-01 1 mL Single-dose vial |
| NDC 0069-1306-10
Carton containing 10 vials |
3,000 Units/mL | NDC 0069-1306-01 1 mL Single-dose vial |
| NDC 0069-1307-10
Carton containing 10 vials |
4,000 Units/mL | NDC 0069-1307-01 1 mL Single-dose vial |
| NDC 0069-1308-10
Carton containing 10 vials |
10,000 Units/mL | NDC 0069-1308-01 1 mL Single-dose vial |
| NDC 0069-1309-10
Carton containing 10 vials |
40,000 Units/mL | NDC 0069-1309-01 1 mL Single-dose vial |
| NDC 0069-1309-04
Carton containing 4 vials |
40,000 Units/mL | NDC 0069-1309-01 1 mL Single-dose vial |
Store at 36°F to 46°F (2°C to 8°C). Do not freeze.
Do not shake. Do not use RETACRIT that has been shaken or frozen.
Store RETACRIT vials in the original carton until use to protect from light.
Manufactured by: Hospira, Inc., a subsidiary of Pfizer Inc., Lake Forest, IL 60045 USA. Revised: Jan 2019
The following serious adverse reactions are discussed in greater detail in other sections of the label:
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 another drug and may not reflect the rates observed in practice.
Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to epoetin alfa. 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 epoetin alfa. 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 epoetin alfa-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:
Table 3. Adverse Reactions in Patients with CKD on Dialysis
| Adverse Reaction | Epoetin alfa-treated Patients (n = 148) |
Placebo-treated Patients (n = 96) |
| Hypertension | 27.7% | 12.5% |
| Arthralgia | 16.2% | 3.1% |
| Muscle spasm | 7.4% | 6.3% |
| Pyrexia | 10.1% | 8.3% |
| Dizziness | 9.5% | 8.3% |
| Medical Device Malfunction (artificial kidney clotting during dialysis) | 8.1% | 4.2% |
| Vascular Occlusion (vascular access thrombosis) | 8.1% | 2.1% |
| Upper respiratory tract infection | 6.8% | 5.2% |
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% epoetin alfa and 1% placebo) [see WARNINGS AND PRECAUTIONS].
The adverse reactions with a reported incidence of ≥ 5% in epoetin alfa-treated patients and that occurred at a ≥ 1% higher frequency than in placebo-treated patients are shown in the table below:
Table 4. Adverse Reactions in Patients with CKD Not on Dialysis
| Adverse Reactions | Epoetin alfa-treated Patients (n = 131) |
Placebo-treated Patients (n = 79) |
| Hypertension | 13.7% | 10.1% |
| Arthralgia | 12.2% | 7.6% |
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% epoetin alfa and 0% placebo) and myocardial infarction (0.8% epoetin alfa and 0% placebo) [see WARNINGS AND PRECAUTIONS].
In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults.
A total of 297 zidovudine-treated patients with HIV-infection were studied in 4 placebo-controlled studies. A total of 144 (48%) patients were randomly assigned to receive epoetin alfa and 153 (52%) patients were randomly assigned to receive placebo. Epoetin alfa was administered at doses between 100 and 200 Units/kg 3 times weekly subcutaneously for up to 12 weeks.
For the combined epoetin alfa 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 epoetin alfa 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 patients with HIV-infection, adverse reactions with an incidence of ≥ 1% in patients treated with epoetin alfa were:
Table 5. Adverse Reactions in Zidovudine-treated Patients with HIV-infection
| Adverse Reaction | Epoetin alfa (n = 144) |
Placebo (n = 153) |
| Pyrexia | 42% | 34% |
| Cough | 26% | 14% |
| Rash | 19% | 7% |
| Injection site irritation | 7% | 4% |
| Urticaria | 3% | 1% |
| Respiratory tract congestion | 1% | Not reported |
| Pulmonary embolism | 1% | Not reported |
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 epoetin alfa 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 epoetin alfa 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 epoetin alfa-treatment group was 158 white (94%) and 10 black (6%). Epoetin alfa 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 epoetin alfa-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:
Table 6. Adverse Reactions in Patients with Cancer
| Adverse Reaction | Epoetin alfa (n = 168) |
Placebo (n = 165) |
| Nausea | 35% | 30% |
| Vomiting | 20% | 16% |
| Myalgia | 10% | 5% |
| Arthralgia | 10% | 6% |
| Stomatitis | 10% | 8% |
| Cough | 9% | 7% |
| Weight decrease | 9% | 5% |
| Leukopenia | 8% | 7% |
| Bone pain | 7% | 4% |
| Rash | 7% | 5% |
| Hyperglycemia | 6% | 4% |
| Insomnia | 6% | 2% |
| Headache | 5% | 4% |
| Depression | 5% | 4% |
| Dysphagia | 5% | 2% |
| Hypokalemia | 5% | 3% |
| Thrombosis | 5% | 3% |
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 epoetin alfa and 103 (22%) patients were randomly assigned to receive placebo. Epoetin alfa 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 epoetin alfa treatment groups, a total of 90 (25%) men and 268 (75%) women between the ages of 29 and 89 years were enrolled. The racial distribution of the combined epoetin alfa 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 epoetin alfa-treated patients that occurred at a higher frequency than in placebo-treated patients are shown in the table below:
Table 7. Adverse Reactions in Surgery Patients
| Adverse Reaction | Study S1 | Study S2 | |||
| Epoetin alfa 300 U/kg (n = 112)a |
Epoetin alfa 100 U/kg (n = 101)a |
Placebo (n = 103)a |
Epoetin alfa 600 U/kg x 4 weeks (n = 73)b |
Epoetin alfa 300 U/kg x 15 days (n = 72)b |
|
| Nausea | 47% | 43% | 45% | 45% | 56% |
| Vomiting | 21% | 12% | 14% | 19% | 28% |
| Pruritus | 16% | 16% | 14% | 12% | 21% |
| Headache | 13% | 11% | 9% | 10% | 18% |
| Injection site pain | 13% | 9% | 8% | 12% | 11% |
| Chills | 7% | 4% | 1% | 1% | 0% |
| Deep vein thrombosis | 6% | 3% | 3% | 0%c | 0%c |
| Cough | 5% | 4% | 0% | 4% | 4% |
| Hypertension | 5% | 3% | 5% | 5% | 6% |
| Rash | 2% | 2% | 1% | 3% | 3% |
| Edema | 1% | 2% | 2% | 1% | 3% |
| a Study included patients undergoing orthopedic surgery treated with epoetin alfa or placebo for 15 days. b Study included patients undergoing orthopedic surgery treated with epoetin alfa 600 U/kg weekly for 4 weeks or 300 U/kg daily for 15 days. c DVTs were determined by clinical symptoms. |
|||||
The following adverse reactions have been identified during post-approval use of epoetin alfa.
Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
As with all therapeutic proteins, there is a potential for immunogenicity. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to epoetin alfa with the incidence of antibodies to other products may be misleading.
Neutralizing antibodies to epoetin alfa that cross-react with endogenous erythropoietin and other ESAs can result in PRCA or severe anemia (with or without other cytopenias) [see WARNINGS AND PRECAUTIONS].
No Information Provided
Included as part of the "PRECAUTIONS" Section
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) |
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.
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 Increased Mortality And/Or Increased Risk Of Tumor Progression Or Recurrence In Patients With Cancer]) 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).
An increased incidence of deep venous thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated [see ADVERSE REACTIONS]. 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].
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.
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*) | Primary Efficacy Outcome | Adverse Outcome for ESA-containing Arm |
| Chemotherapy | ||||
| Study 1 Metastatic breast cancer (n = 2098) |
≤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 |
|
* Q1 = 25th percentile Q3 = 75th percentile † This 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. |
||||
Study 2 was described in the previous section [see Increased Mortality, Myocardial Infarction, Stroke, And Thromboembolism]. 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).
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).
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).
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 INFORMATION].
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.
For lack or loss of hemoglobin response to RETACRIT, 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 [see Pure Red Cell Aplasia]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to RETACRIT therapy [see DOSAGE AND ADMINISTRATION].
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, 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.
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.
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.
Patients may require adjustments in their dialysis prescriptions after initiation of RETACRIT. Patients receiving RETACRIT may require increased anticoagulation with heparin to prevent clotting of the extracorporeal circuit during hemodialysis.
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
The carcinogenic potential of epoetin alfa products has not been evaluated.
Epoetin alfa was not mutagenic or clastogenic under the conditions tested: epoetin alfa was negative in the in vitro bacterial reverse mutation assay (Ames test), in the in vitro mammalian cell gene mutation assay (the hypoxanthine-guanine phosphoribosyl transferase [HGPRT] locus), in an in vitro chromosomal aberration assay in mammalian cells, and in the in vivo mouse micronucleus assay.
When administered intravenously to male and female rats prior to and during mating, and to females through the beginning of implantation (up to gestational day 7; dosing stopped prior to the beginning of organogenesis), doses of 100 and 500 Units/kg/day of epoetin alfa caused slight increases in pre-implantation loss, post-implantation loss and decreases in the incidence of live fetuses. It is not clear whether these effects reflect a drug effect on the uterine environment or on the conceptus. This animal dose level of 100 Units/kg/day approximates the clinical recommended starting dose, depending on the patient’s treatment indication, but may be lower than the clinical dose in patients whose doses have been adjusted.
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 (see Data). Consider the benefits and risks of RETACRIT single-dose vials for the mother and possible risks to the fetus when prescribing RETACRIT to a pregnant woman.
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.
Human Data
There are reports of pregnant women with anemia alone or anemia associated with severe renal disease and other hematologic disorders who received epoetin alfa. 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. 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, presence or absence of adverse outcomes.
Animal Data
When rats received epoetin alfa at doses greater than or equal to 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 in the presence of maternal toxicity (red limbs/pinna, focal splenic capsular toxicity, increased organ weights). This animal dose level of 100 Units/kg/day may approximate the clinical recommended starting dose, depending on the treatment indication. When pregnant rats and rabbits received intravenous doses of up to 500 mg/kg/day of epoetin alfa only during organogenesis (gestational days 7 to 17 in rats and gestational days 6 to 18 in rabbits), no teratogenic effects were observed in the offspring. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no epoetin alfa-related effects were apparent for their offspring (F2 generation fetuses).
When pregnant rats received epoetin alfa at doses of 500 Units/kg/day late in pregnancy (after the period of organogenesis from day 17 of gestation through day 21 of lactation), pups exhibited decreased number of caudal vertebrae, decreased body weight gain, and delayed appearance of abdominal hair, eyelid opening, and ossification in the presence of maternal toxicity (red limbs/pinna, increased organ weights). This animal dose level of 500 U/kg/day is approximately five times the clinical recommended starting dose depending on the patient’s treatment indication.
There is no information regarding the presence of epoetin alfa products in human milk, the effects on the breastfed infant, or the effects on milk production. However, endogenous erythropoietin is present in human milk. Because many drugs are present in human milk, caution should be exercised when RETACRIT is administered to a lactating woman.
RETACRIT 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 [see Clinical Studies].
Use of epoetin alfa products in pediatric patients with CKD not requiring dialysis is supported by efficacy in pediatric patients requiring dialysis. The mechanism of action of epoetin alfa products is the same for these two populations. Published literature also has reported the use of epoetin alfa in pediatric patients with CKD not requiring dialysis. Dose-dependent increases in hemoglobin and hematocrit were observed with reductions in transfusion requirements.
The safety data from the pediatric studies and postmarketing reports are similar to those obtained from the studies of epoetin alfa in adult patients with CKD [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. Postmarketing reports do not indicate a difference in safety profiles in pediatric patients with CKD requiring dialysis and not requiring dialysis.
RETACRIT 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 [see Clinical Studies]. The safety data from these studies are similar to those obtained from the studies of epoetin alfa in adult patients with cancer [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS].
Published literature has reported the use of epoetin alfa 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.
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.
Of the 4553 patients who received epoetin alfa 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 epoetin alfa 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].
Among 778 patients enrolled in the 3 clinical studies of epoetin alfa for the treatment of anemia due to concomitant chemotherapy, 419 received epoetin alfa and 359 received placebo. Of the 419 who received epoetin alfa, 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 epoetin alfa in geriatric and younger patients within the 3 studies were similar.
Among 1731 patients enrolled in the 6 clinical studies of epoetin alfa for reduction of allogeneic RBC transfusions in patients undergoing elective surgery, 1085 received epoetin alfa and 646 received placebo or standard of care treatment. Of the 1085 patients who received epoetin alfa, 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 epoetin alfa 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 epoetin alfa for the treatment of patients treated with zidovudine for HIV-infection to determine whether they respond differently from younger patients.
RETACRIT overdosage can cause hemoglobin levels above the desired level, which should be managed with discontinuation or reduction of RETACRIT dosage and/or with phlebotomy, as clinically indicated [see CLINICAL PHARMACOLOGY]. Cases of severe hypertension have been observed following overdose with ESAs [see WARNINGS AND PRECAUTIONS].
RETACRIT is contraindicated in patients with:
Epoetin alfa products stimulate erythropoiesis by the same mechanism as endogenous erythropoietin.
Epoetin alfa products increase the reticulocyte count within 10 days of initiation, followed by increases in the RBC count, hemoglobin, and hematocrit, usually within 2 to 6 weeks. The rate of hemoglobin increase varies among patients and is dependent upon the dose of epoetin alfa products administered. For correction of anemia in hemodialysis patients, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly.
In adult and pediatric patients with CKD, the elimination half-life (t1/2) of plasma erythropoietin after intravenous administration of epoetin alfa ranged from 4 to 13 hours. After subcutaneous administration, Cmax was achieved within 5 to 24 hours. The t1/2 in adult patients with serum creatinine greater than 3 mg/dL was similar between those not on dialysis and those maintained on dialysis. The pharmacokinetic data indicate no apparent difference in epoetin alfa t1/2 among adult patients above or below 65 years of age.
A pharmacokinetic study comparing 150 Units/kg subcutaneous 3 times weekly to 40,000 Units subcutaneous weekly dosing regimen was conducted for 4 weeks in healthy subjects (n = 12) and for 6 weeks in anemic cancer patients (n = 32) receiving cyclic chemotherapy. There was no accumulation of serum erythropoietin after the 2 dosing regimens during the study period. The 40,000 Units weekly regimen had a higher Cmax (3-to 7-fold), longer Tmax (2-to 3-fold), higher AUC0-168 h (2-to 3-fold) of erythropoietin and lower clearance (CL) (50%) than the 150 Units/kg 3 times weekly regimen. In anemic cancer patients, the average t1/2 was similar (40 hours with range of 16 to 67 hours) after both dosing regimens. After the 150 Units/kg 3 times weekly dosing, the values of Tmax and CL were similar (13.3 ± 12.4 vs. 14.2 ± 6.7 hours, and 20.2 ± 15.9 vs. 23.6 ± 9.5 mL/hr/kg) between week 1 when patients were receiving chemotherapy (n = 14) and week 3 when patients were not receiving chemotherapy (n = 4). Differences were observed after the 40,000 Units weekly dosing with longer Tmax (38 ± 18 hours) and lower CL (9.2 ± 4.7 mL/hr/kg) during week 1 when patients were receiving chemotherapy (n = 18) compared with those (22 ± 4.5 hours, 13.9 ± 7.6 mL/hr/kg, respectively) during week 3 when patients were not receiving chemotherapy (n = 7).
The pharmacokinetic profile of epoetin alfa in pediatric patients appeared similar to that of adults.
The pharmacokinetics of epoetin alfa products has not been studied in patients with HIV-infection.
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.
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.
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].
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].
The safety and efficacy of epoetin alfa were evaluated in 4 placebo-controlled studies enrolling 297 anemic patients (hemoglobin < 10 g/dL) with HIV-infection receiving concomitant therapy with zidovudine. In the subgroup of patients (89/125 epoetin alfa and 88/130 placebo) with pre-study endogenous serum erythropoietin levels ≤ 500 mUnits/mL, epoetin alfa reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group. Among those patients who required RBC transfusions at baseline, 43% of patients treated with epoetin alfa versus 18% of placebo-treated patients were RBC transfusion-independent during the second and third months of therapy. Epoetin alfa therapy also resulted in significant increases in hemoglobin in comparison to placebo. When examining the results according to the weekly dose of zidovudine received during month 3 of therapy, there was a statistically significant reduction (p < 0.003) in RBC transfusion requirements in patients treated with epoetin alfa (n = 51) compared to placebo-treated patients (n = 54) whose mean weekly zidovudine dose was ≤ 4200 mg/week.
Approximately 17% of the patients with endogenous serum erythropoietin levels ≤ 500 mUnits/mL receiving epoetin alfa in doses from 100 to 200 Units/kg 3 times weekly achieved a hemoglobin of 12.7 g/dL without administration of RBC transfusions or significant reduction in zidovudine dose. In the subgroup of patients whose pre-study endogenous serum erythropoietin levels were > 500 mUnits/mL, epoetin alfa therapy did not reduce RBC transfusion requirements or increase hemoglobin compared to the corresponding responses in placebo-treated patients.
The safety and effectiveness of epoetin alfa was assessed in two multicenter, randomized (1:1), placebo-controlled, double-blind studies (Study C1 and Study C2) and a pooled analysis of six additional randomized (1:1), multicenter, placebo-controlled, double-blind studies. All studies were conducted in patients with anemia due to concomitantly administered cancer chemotherapy. Study C1 enrolled 344 adult patients, Study C2 enrolled 222 pediatric patients, and the pooled analysis contained 131 patients randomized to epoetin alfa or placebo. In Studies C1 and C2, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion, from week 5 through end of the study, with the last-known RBC transfusion status carried forward for patients who discontinued treatment. In the pooled analysis, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion from week 5 through end of the study in the subset of patients who were remaining on therapy for 6 or more weeks.
Study C1 was conducted in patients with anemia (hemoglobin < 11.5 g/dL for males; < 10.5 g/dL for females) with non-myeloid malignancies receiving myelosuppressive chemotherapy. Randomization was stratified by type of malignancy (lung vs. breast vs. other), concurrent radiation therapy planned (yes or no), and baseline hemoglobin (< 9 g/dL vs. ≥ 9 g/dL); patients were randomized to epoetin alfa 40,000 Units (n = 174) or placebo (n = 170) as a weekly subcutaneous injection commencing on the first day of the chemotherapy cycle.
Ninety-one percent of patients were white, 44% were male, and the median age of patients was 66 years (range: 20 to 88 years). The proportion of patients withdrawn from the study prior to week 5 was less than 10% for placebo-treated or epoetin-treated patients. Per protocol, the last available hemoglobin values from patients who dropped out were included in the efficacy analyses. Efficacy results are shown in Table 9.
Table 9. Study C1: Proportion of Patients Transfused
| Chemotherapy Regimen | Week 5 Through Week 16 or End of Studya | |
| Epoetin alfa (n = 174) |
Placebo (n = 170) |
|
| All Regimens | 14% (25/174)b | 28% (48/170) |
| Regimens without cisplatin | 14% (21/148) | 26% (35/137) |
| Regimens containing cisplatin | 15% (4/26) | 39% (13/33) |
|
a Last-known RBC transfusion status carried forward for patients who discontinued treatment b Two-sided p < 0.001, logistic regression analysis adjusting for accrual rate and stratification variables. |
||
Study C2 was conducted in 222 patients with anemia, ages 5 to 18, receiving chemotherapy for the treatment of various childhood malignancies. Randomization was stratified by cancer type (solid tumors, Hodgkin’s disease, acute lymphocytic leukemia, vs. non-Hodgkin’s lymphoma); patients were randomized to receive epoetin alfa at 600 Units/kg maximum 40,000 Units (n = 111) or placebo (n = 111) as a weekly intravenous injection.
Sixty-nine percent of patients were white, 55% were male, and the median age of patients was 12 years (range: 5 to 18 years). Two (2%) of placebo-treated patients and 3 (3%) of epoetin alfa-treated patients dropped out of the study prior to week 5. There were fewer RBC transfusions from week 5 through the end-of-study in epoetin alfa-treated patients [51% (57/111)] compared to placebo-treated patients [69% (77/111)]. There was no evidence of an improvement in health-related quality of life, including no evidence of an effect on fatigue, energy, or strength in patients receiving epoetin alfa as compared to those receiving placebo.
The results of 6 studies of similar design and that randomized 131 patients to epoetin alfa or placebo were pooled to assess the safety and effectiveness of epoetin alfa. Patients were randomized to receive epoetin alfa at 150 Units/kg (n = 63) or placebo (n = 68), subcutaneously three times per week for 12 weeks in each study. Across all studies, 72 patients were treated with concomitant non cisplatin-containing chemotherapy regimens and 59 patients were treated with concomitant cisplatin-containing chemotherapy regimens. Twelve patients (19%) in the epoetin alfa arm and 10 patients (15%) in the placebo-arm dropped out prior to week 6 and are excluded from efficacy analyses.
Table 10. Proportion of Patients Transfused in the Pooled Analysis for Three Times Per Week
| Chemotherapy Regimen | Week 5 Through Week 12 or End of Studya | |
| Epoetin alfa | Placebo | |
| All Regimens | 22% (11/51)b | 43% (25/58) |
| Regimens without cisplatin | 21% (6/29) | 33% (11/33) |
| Regimens containing cisplatin | 23% (5/22) | 56% (14/25) |
|
a Limited to patients remaining on study beyond week 6 and includes only RBC transfusions during weeks 5-12. b Two-sided p < 0.05, unadjusted. |
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The safety and efficacy of epoetin alfa were evaluated in a placebo-controlled, double-blind study (S1) enrolling 316 patients scheduled for major, elective orthopedic hip or knee surgery who were expected to require ≥ 2 units of blood and who were not able or willing to participate in an autologous blood donation program. Patients were stratified into 1 of 3 groups based on their pretreatment hemoglobin [≤ 10 g/dL (n = 2), > 10 to ≤ 13 g/dL (n = 96), and > 13 to ≤ 15 g/dL (n = 218)] and then randomly assigned to receive 300 Units/kg epoetin alfa, 100 Units/kg epoetin alfa, or placebo by subcutaneous injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery. All patients received oral iron and a low-dose, postoperative warfarin regimen.
Treatment with epoetin alfa 300 Units/kg significantly (p = 0.024) reduced the risk of allogeneic RBC transfusion in patients with a pretreatment hemoglobin of > 10 to ≤ 13 g/dL; 5/31 (16%) of patients treated with epoetin alfa 300 Units/kg, 6/26 (23%) of patients treated with epoetin alfa 100 Units/kg, and 13/29 (45%) of placebo-treated patients were transfused. There was no significant difference in the number of patients transfused between epoetin alfa (9% 300 Units/kg, 6% 100 Units/kg) and placebo (13%) in the > 13 to ≤ 15 g/dL hemoglobin stratum. There were too few patients in the ≤ 10 g/dL group to determine if epoetin alfa is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per epoetin alfa-treated patient (0.45 units blood for 300 Units/kg, 0.42 units blood for 100 Units/kg) was less than the mean transfused per placebo-treated patient (1.14 units) (overall p = 0.028). In addition, mean hemoglobin, hematocrit, and reticulocyte counts increased significantly during the presurgery period in patients treated with epoetin alfa.
Epoetin alfa was also evaluated in an open-label, parallel-group study (S2) enrolling 145 patients with a pretreatment hemoglobin level of ≥ 10 to ≤ 13 g/dL who were scheduled for major orthopedic hip or knee surgery and who were not participating in an autologous program. Patients were randomly assigned to receive 1 of 2 subcutaneous dosing regimens of epoetin alfa (600 Units/kg once weekly for 3 weeks prior to surgery and on the day of surgery, or 300 Units/kg once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery). All patients received oral iron and appropriate pharmacologic anticoagulation therapy.
From pretreatment to presurgery, the mean increase in hemoglobin in the 600 Units/kg weekly group (1.44 g/dL) was greater than that observed in the 300 Units/kg daily group. The mean increase in absolute reticulocyte count was smaller in the weekly group (0.11 x 106/mm3) compared to the daily group (0.17 x 106/mm3). Mean hemoglobin levels were similar for the 2 treatment groups throughout the postsurgical period.
The erythropoietic response observed in both treatment groups resulted in similar RBC transfusion rates [11/69 (16%) in the 600 Units/kg weekly group and 14/71 (20%) in the 300 Units/kg daily group]. The mean number of units transfused per patient was approximately 0.3 units in both treatment groups.
RETACRIT™
(Ret-uh-krit)
(epoetin alfa-epbx)
Read this Medication Guide:
This Medication Guide does not take the place of talking to your healthcare provider about your medical condition or your treatment. Talk with your healthcare provider regularly about the use of RETACRIT and ask if there is new information about RETACRIT.
What is the most important information I should know about RETACRIT?
RETACRIT may cause serious side effects that can lead to death, including:
For people with cancer:
For all people who take RETACRIT, including people with cancer or chronic kidney disease:
See “What are the possible side effects of RETACRIT?” below for more information.
If you decide to take RETACRIT, your healthcare provider should prescribe the smallest dose of RETACRIT that is necessary to reduce your chance of needing RBC transfusions.
What is RETACRIT?
RETACRIT is a prescription medicine used to treat anemia. People with anemia have a lower-thannormal number of RBCs. RETACRIT works like the human protein called erythropoietin to help your body make more RBCs. RETACRIT is used to reduce or avoid the need for RBC transfusions.
RETACRIT may be used to treat anemia if it is caused by:
RETACRIT may also be used to reduce the chance you will need RBC transfusions if you are scheduled for certain surgeries where a lot of blood loss is expected.
If your hemoglobin level stays too high or if your hemoglobin goes up too quickly, this may lead to serious health problems which may result in death. These serious health problems may happen if you take RETACRIT, even if you do not have an increase in your hemoglobin level.
RETACRIT has not been proven to improve quality of life, fatigue, or well-being.
RETACRIT should not be used for treatment of anemia:
RETACRIT should not be used to reduce the chance you will need RBC transfusions if:
It is not known if RETACRIT is safe and effective in treating anemia in children less than 1 month old who have chronic kidney disease and in children less than 5 years old who have anemia caused by chemotherapy.
Who should not take RETACRIT?
Do not take RETACRIT if you:
Before taking RETACRIT, tell your healthcare provider about all of your medical conditions, including if you:
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements.
How should I take RETACRIT?
What are the possible side effects of RETACRIT?
RETACRIT may cause serious side effects, including:
Common side effects of RETACRIT include:
These are not all of the possible side effects of RETACRIT. Your healthcare provider can give you a more complete list. Tell your healthcare provider about any side effects that bother you or that do not go away.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store RETACRIT?
Keep RETACRIT and all medicines out of the reach of children.
General information about RETACRIT.
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use RETACRIT for a condition for which it was not prescribed. Do not give RETACRIT to other people even if they have the same symptoms that you have. It may harm them. You can ask your healthcare provider or pharmacist for information about RETACRIT that is written for healthcare professionals.
What are the ingredients in RETACRIT?
Active Ingredient: epoetin alfa-epbx
Inactive Ingredients:
Instructions for Use
RETACRIT™
(Ret-uh-krit)
(epoetin alfa-epbx)
Use these Instructions for Use if you or your caregiver has been trained to give RETACRIT injections at home. Do not give yourself the injection unless you have received training from your healthcare provider. If you are not sure about giving the injection or you have questions, ask your healthcare provider for help.
Before reading these Instructions for Use, read the Medication Guide that comes with RETACRIT for the most important information you need to know.
When you receive your RETACRIT vial make sure that:
How should I prepare for an injection of RETACRIT?
Only use disposable syringes and needles. Use the syringes and needles only one time and then throw them away as instructed by your healthcare provider.
Important: Follow these instructions exactly to help avoid infections.
Preparing the dose:
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Selecting and preparing the injection site:
RETACRIT can be injected into your body using two different ways (routes) as described below. Follow your healthcare provider’s instructions about how you should inject RETACRIT. In patients on hemodialysis, the intravenous (IV) route is recommended.
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How should I dispose of the vials, syringes, and needles?
Do not reuse the single-dose vials, syringes, or needles. Throw away the vials, syringes, and needles as instructed by your healthcare provider or by following these steps:
Keep RETACRIT and all medicines out of reach of children.
These Instructions for Use have been approved by the U.S. Food and Drug Administration.
