Retacrit
epoetin alfa-epbx · Injection, Solution · Intravenous, Subcutaneous
• In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL ( 5.1 ).
• No trial has identified a hemoglobin target level, ESA dose, or dosing strategy that does not increase these risks ( 2.2 ).
• Use the lowest RETACRIT dose sufficient to reduce the need for red blood cell (RBC) transfusions ( 5.1 ). Cancer:
• …
Uses
1 INDICATIONS AND USAGE RETACRIT is an erythropoiesis-stimulating agent (ESA) indicated for:
• Treatment of anemia due to o Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis ( 1.1 ). o Zidovudine in patients with Human Immunodeficiency Virus (HIV) infection ( 1.2 ). o The effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy ( 1.3 ).
• Reduction of allogeneic red blood cell (RBC) transfusions in patients undergoing elective, noncardiac, nonvascular surgery ( 1.4 ). Limitations of Use RETACRIT has not been shown to improve quality of life, fatigue, or patient well-being ( 1.5 ). 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 ).
• In patients with cancer receiving myelosuppressive chemotherapy when the anticipated outcome is cure ( 1.5 ).
• In patients with cancer receiving myelosuppressive chemotherapy in whom the anemia can be managed by transfusion ( 1.5 ).
• In patients scheduled for surgery who are willing to donate autologous blood ( 1.5 ).
• In patients undergoing cardiac or vascular surgery ( 1.5 ).
• As a substitute for RBC transfusions in patients who require immediate correction of anemia ( 1.5 ). 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. 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. 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. 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. 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.
Dosage and administration
• Evaluate iron status before and during treatment and maintain iron repletion. Correct or exclude other causes of anemia before initiating treatment ( 2.1 ).
• In pregnant women, lactating women, neonates, infants: Use only single-dose vials ( 2.1 ).
• 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 on Zidovudine due to HIV infection: 100 Units/kg 3 times weekly ( 2.3 ).
• 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 ).
• Surgery Patients: 300 Units/kg per day daily for 15 days or 600 Units/kg weekly ( 2.5 ). 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) ] . 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 Warning and Clinical Studies (14) ] . For all patients with CKD: When initiating or adjusting therapy, monitor hemoglobin levels at least weekly until stable, then monitor at least monthly. When adjusting therapy consider hemoglobin rate of rise, rate of decline, ESA responsiveness and hemoglobin variability. A single hemoglobin excursion may not require a dosing change.
• Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.
• If the hemoglobin rises rapidly (e.g., more than 1 g/dL in any 2-week period), reduce the dose of 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: o The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion and, o Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal
• If the hemoglobin level exceeds 10 g/dL, reduce or interrupt the dose of 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). 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.
Dosage forms and strengths
Injection
• 2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, and 10,000 Units/mL in single-dose vials ( 3 ).
• 20,000 Units/2 mL (10,000 Units/mL) and 20,000 Units/mL in multiple-dose vials containing benzyl alcohol ( 3 ). Injection:
• 2,000 Units/mL, 3,000 Units/mL, 4,000 Units/mL, and 10,000 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).
Contraindications
• Uncontrolled hypertension ( 4 ).
• Pure red cell aplasia (PRCA) that begins after treatment with RETACRIT or other erythropoietin protein drugs ( 4 ).
• Serious allergic reactions to RETACRIT or other epoetin alfa products ( 4 ).
• Use of the multiple-dose vials containing benzyl alcohol in neonates, infants, pregnant women, and lactating women ( 4 ). RETACRIT is contraindicated in patients with:
• Uncontrolled hypertension [see Warnings and Precautions (5.3) ] .
• Pure red cell aplasia (PRCA) that begins after treatment with RETACRIT or other erythropoietin protein drugs [see Warnings and Precautions (5.6) ] .
• Serious allergic reactions to RETACRIT or other epoetin alfa products [see Warnings and Precautions (5.7) ] . RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated in:
• Neonates, infants, pregnant women, and lactating women [see Warnings and Precautions (5.9) , Use in Specific Populations (8.1 , 8.2 and 8.4) ] .
Warnings and precautions
• Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism: Using ESAs to target a hemoglobin level of greater than 11 g/dL increases the risk of serious adverse cardiovascular reactions and has not been shown to provide additional benefit ( 5.1 and 14.1 ). Use caution in patients with coexistent cardiovascular disease and stroke ( 5.1 ).
• Increased Mortality and/or Increased Risk of Tumor Progression or Recurrence in Patients with Cancer ( 5.2 ).
• Hypertension: Control hypertension prior to initiating and during treatment with RETACRIT ( 5.3 ).
• Seizures: Epoetin alfa products increase the risk for seizures in patients with CKD ( 5.4 ). Increase monitoring of these patients for changes in seizure frequency or premonitory symptoms ( 5.4 ).
• PRCA: If severe anemia and low reticulocyte count develop during RETACRIT treatment, withhold RETACRIT and evaluate for PRCA ( 5.6 ).
• Serious Allergic Reactions: Discontinue RETACRIT and manage reactions ( 5.7 ).
• Severe Cutaneous Reactions: Discontinue RETACRIT ( 5.8 ).
• Phenylketonurics: Contains phenylalanine ( 5.10 ). 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.
Side effects
The following serious adverse reactions are discussed in greater detail in other sections of the label:
• Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions (5.1) ]
• Increased mortality and/or increased risk of tumor progression or recurrence in Patients with Cancer [see Warnings and Precautions (5.2) ]
• Hypertension [see Warnings and Precautions (5.3) ]
• Seizures [see Warnings and Precautions (5.4) ]
• PRCA [see Warnings and Precautions (5.6) ]
• Serious allergic reactions [see Warnings and Precautions (5.7) ]
• Severe Cutaneous Reactions [see Warnings and Precautions (5.8) ]
• Patients with CKD: Adverse reactions in ≥ 5% of epoetin alfa-treated patients in clinical studies were hypertension, arthralgia, muscle spasm, pyrexia, dizziness, medical device malfunction, vascular occlusion, and upper respiratory tract infection ( 6.1 ).
• Patients on Zidovudine due to HIV infection: Adverse reactions in ≥ 5% of epoetin alfa-treated patients in clinical studies were pyrexia, cough, rash, and injection site irritation ( 6.1 ).
• Patients with Cancer on Chemotherapy: Adverse reactions in ≥ 5% of epoetin alfa-treated patients in clinical studies were nausea, vomiting, myalgia, arthralgia, stomatitis, cough, weight decrease, leukopenia, bone pain, rash, hyperglycemia, insomnia, headache, depression, dysphagia, hypokalemia, and thrombosis ( 6.1 ).
• Surgery Patients: Adverse reactions in ≥ 5% of epoetin alfa-treated patients in clinical studies were nausea, vomiting, pruritus, headache, injection site pain, chills, deep vein thrombosis, cough, and hypertension ( 6.1 ). To report SUSPECTED ADVERSE REACTIONS, contact Hospira, Inc., a Pfizer Company, at 1-800-438-1985, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of other drugs and may not reflect the rates observed in practice. Patients with Chronic Kidney Disease Adult Patients Three double-blind, placebo-controlled studies, including 244 patients with CKD on dialysis, were used to identify the adverse reactions to 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 (5.1) ] . 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 (5.1) ] . Pediatric Patients In pediatric patients with CKD on dialysis, the pattern of adverse reactions was similar to that found in adults. Zidovudine-treated Patients with HIV Infection 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.
Use in specific populations
8.1 Pregnancy Risk Summary RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated in pregnant women [see Contraindications (4) ] . When therapy with RETACRIT is needed during pregnancy, use a benzyl alcohol-free formulation (i.e., single-dose vial). Do not mix RETACRIT with bacteriostatic saline when administering to pregnant women because it contains benzyl alcohol (see Clinical Considerations ) [see Dosage and Administration (2.1) ] . 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. Clinical Considerations Fetal/Neonatal Adverse Reactions The multiple-dose vials of RETACRIT contain benzyl alcohol. The preservative benzyl alcohol has been associated with serious adverse reactions and death when administered intravenously to neonates and infants [see Warnings and Precautions (5.9) , Use in Specific Populations (8.4) ] . There is a potential for similar risks to fetuses exposed to benzyl alcohol in utero. Data 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. 8.2 Lactation Risk Summary RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated in lactating women [see Contraindications (4) , Warnings and Precautions (5.9) ] . Advise a lactating woman not to breastfeed for at least 2 weeks after the last dose. The preservative benzyl alcohol has been associated with serious adverse reactions and death when administered intravenously to neonates and infants [see Use in Specific Populations (8.4) ] . There is a potential for similar risks to infants exposed to benzyl alcohol through human milk. Do not mix RETACRIT with bacteriostatic saline containing benzyl alcohol, if administering RETACRIT to a lactating woman [see Dosage and Administration (2.1) ] . 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. 8.4 Pediatric Use The multiple-dose vials are formulated with benzyl alcohol and are contraindicated for use in neonates and infants [see Contraindications (4) , Warnings and Precautions (5.9) ] . When therapy with RETACRIT is needed in neonates and infants, use the single-dose vial, which is a benzyl alcohol-free formulation. Do not mix the single-dose vials with bacteriostatic saline when administering RETACRIT to neonates or infants because it contains benzyl alcohol [see Dosage and Administration (2.6) ] . Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative.
Pregnancy
8.1 Pregnancy Risk Summary RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated in pregnant women [see Contraindications (4) ] . When therapy with RETACRIT is needed during pregnancy, use a benzyl alcohol-free formulation (i.e., single-dose vial). Do not mix RETACRIT with bacteriostatic saline when administering to pregnant women because it contains benzyl alcohol (see Clinical Considerations ) [see Dosage and Administration (2.1) ] . 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. Clinical Considerations Fetal/Neonatal Adverse Reactions The multiple-dose vials of RETACRIT contain benzyl alcohol. The preservative benzyl alcohol has been associated with serious adverse reactions and death when administered intravenously to neonates and infants [see Warnings and Precautions (5.9) , Use in Specific Populations (8.4) ] . There is a potential for similar risks to fetuses exposed to benzyl alcohol in utero. Data 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.
Pediatric use
8.4 Pediatric Use The multiple-dose vials are formulated with benzyl alcohol and are contraindicated for use in neonates and infants [see Contraindications (4) , Warnings and Precautions (5.9) ] . When therapy with RETACRIT is needed in neonates and infants, use the single-dose vial, which is a benzyl alcohol-free formulation. Do not mix the single-dose vials with bacteriostatic saline when administering RETACRIT to neonates or infants because it contains benzyl alcohol [see Dosage and Administration (2.6) ] . Serious adverse reactions including fatal reactions and the "gasping syndrome" occurred in premature neonates and infants in the neonatal intensive care unit who received drugs containing benzyl alcohol as a preservative. In these cases, benzyl alcohol dosages of 99 to 234 mg/kg/day produced high levels of benzyl alcohol and its metabolites in the blood and urine (blood levels of benzyl alcohol were 0.61 to 1.378 mmol/L). Additional adverse reactions included gradual neurological deterioration, seizures, intracranial hemorrhage, hematologic abnormalities, skin breakdown, hepatic and renal failure, hypotension, bradycardia, and cardiovascular collapse. Preterm, low birth weight infants may be more likely to develop these reactions because they may be less able to metabolize benzyl alcohol. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Warnings and Precautions (5.9) ] . Pediatric Patients with CKD 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 (14.1) ] . Use of RETACRIT in pediatric patients with CKD not requiring dialysis is supported by efficacy of epoetin alfa 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 (5) and Adverse Reactions (6.1) ] . Postmarketing reports do not indicate a difference in safety profiles in pediatric patients with CKD requiring dialysis and not requiring dialysis. Pediatric Patients with Cancer on Chemotherapy 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 (14.3) ] . 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 (5.1 , 5.2) and Adverse Reactions (6.1) ] . Pediatric Patients with HIV Infection Receiving Zidovudine 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. Pharmacokinetics in Neonates Limited pharmacokinetic data from a study of 7 preterm, very low birth weight neonates and 10 healthy adults given intravenous erythropoietin suggested that distribution volume was approximately 1.5 to 2 times higher in the preterm neonates than in the healthy adults, and clearance was approximately 3 times higher in the preterm neonates than in the healthy adults.
Geriatric use
8.5 Geriatric Use 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 (2) ] . 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.
Overdosage
10 OVERDOSAGE 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 (12.2) ] . Cases of severe hypertension have been observed following overdose with ESAs [see Warnings and Precautions (5.3) ] .
Description
Epoetin alfa-epbx is an erythropoiesis-stimulating agent. Epoetin alfa-epbx is a 165-amino acid 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 vials in multiple formulations. 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. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 7.0 – 7.5). Each 1 mL multiple-dose vial of 20,000 Units of epoetin alfa-epbx contains benzyl alcohol (8.5 mg), L-methionine (0.45 mg), polysorbate 20 (0.04 mg), sodium phosphate dibasic anhydrous (0.09 mg), sodium phosphate monobasic monohydrate (2.67 mg), and sucrose (60 mg) in Water for Injection, USP. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 5.6 – 6.6). Each 2 mL multiple-dose vial of 20,000 Units (10,000 Units/mL) of epoetin alfa-epbx contains benzyl alcohol (17 mg), L-methionine (0.9 mg), polysorbate 20 (0.08 mg), sodium phosphate dibasic anhydrous (0.18 mg), sodium phosphate monobasic monohydrate (5.34 mg), and sucrose (120 mg) in Water for Injection, USP. Sodium hydroxide and hydrochloric acid may be added to adjust the pH (pH 5.6 – 6.6).
Mechanism of action
12.1 Mechanism of Action Epoetin alfa products stimulate erythropoiesis by the same mechanism as endogenous erythropoietin.
How supplied
(epoetin alfa-epbx) injection is a sterile, clear, and colorless solution in single-dose and multiple-dose vials available as: Unit of Sale Strength Each Single Unit of Use NDC 59353-002-10 Carton containing 10 vials 2,000 Units/mL NDC 59353-002-01 1 mL Single-dose vial NDC 59353-003-10 Carton containing 10 vials 3,000 Units/mL NDC 59353-003-01 1 mL Single-dose vial NDC 59353-004-10 Carton containing 10 vials 4,000 Units/mL NDC 59353-004-01 1 mL Single-dose vial NDC 59353-010-10 Carton containing 10 vials 10,000 Units/mL NDC 59353-010-01 1 mL Single-dose vial NDC 59353-120-10 Carton containing 10 vials with a freeze strip indicator 20,000 Units/mL NDC 59353-120-01 1 mL Multiple-dose vial NDC 59353-220-10 Carton containing 10 vials with a freeze strip indicator 20,000 Units/ 2 mL (10,000 Units/mL) NDC 59353-220-01 2 mL Multiple-dose vial Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. When exposed to freezing temperatures, the green area of the freeze strip indicator in the carton of the multiple-dose vials will show signs of cloudy or white discoloration. Do not shake. Do not use RETACRIT that has been shaken or frozen or if the green area of the freeze strip indicator is cloudy or white. Store RETACRIT vials in the original carton until use to protect from light. The vial stopper used for RETACRIT is not made with natural rubber latex.
Storage
Store refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. When exposed to freezing temperatures, the green area of the freeze strip indicator in the carton of the multiple-dose vials will show signs of cloudy or white discoloration. Do not shake. Do not use RETACRIT that has been shaken or frozen or if the green area of the freeze strip indicator is cloudy or white. Store RETACRIT vials in the original carton until use to protect from light. The vial stopper used for RETACRIT is not made with natural rubber latex.
Patient information
Advise the patient to read the FDA-approved patient labeling (Medication Guide and Instructions for Use) . Inform patients:
• Of the increased risks of mortality, serious cardiovascular reactions, thromboembolic reactions, stroke, and tumor progression [see Warnings and Precautions (5.1 , 5.2) ] .
• To undergo regular blood pressure monitoring, adhere to prescribed anti-hypertensive regimen and follow recommended dietary restrictions.
• To contact their healthcare provider for new-onset neurologic symptoms or change in seizure frequency.
• Of the need to have regular laboratory tests for hemoglobin.
• Risks are associated with benzyl alcohol in neonates, infants, pregnant women, and lactating women [see Use in Specific Populations (8.1 , 8.2 , 8.4) ]. Instruct patients who self-administer RETACRIT of the:
• Importance of following the Instructions for Use.
• Dangers of reusing needles, syringes, or unused portions of single-dose vials.
• Proper disposal of used syringes, needles, and unused vials, and of the full container.
Label text from the FDA structured product label by Vifor (International) Inc. (revised Jun 22, 2025). Long sections are shortened; the complete label is on DailyMed.
Active ingredients
- Epoetin in 13 products
Retacrit NDC products (13)
| NDC | Strength & form | Labeler | Type |
|---|---|---|---|
| 0069-1305 | Epoetin 2000 [iU]/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | BLA |
| 0069-1306 | Epoetin 3000 [iU]/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | BLA |
| 0069-1307 | Epoetin 4000 [iU]/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | BLA |
| 0069-1308 | Epoetin 10000 [iU]/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | BLA |
| 0069-1309 | Epoetin 40000 [iU]/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | BLA |
| 0069-1311 | Epoetin 20000 [iU]/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | BLA |
| 0069-1318 | Epoetin 10000 [iU]/mL Injection, Solution | Pfizer Laboratories Div Pfizer Inc | BLA |
| 59353-002 | Epoetin 2000 [iU]/mL Injection, Solution | Vifor (International) Inc. | BLA |
| 59353-003 | Epoetin 3000 [iU]/mL Injection, Solution | Vifor (International) Inc. | BLA |
| 59353-004 | Epoetin 4000 [iU]/mL Injection, Solution | Vifor (International) Inc. | BLA |
| 59353-010 | Epoetin 10000 [iU]/mL Injection, Solution | Vifor (International) Inc. | BLA |
| 59353-120 | Epoetin 20000 [iU]/mL Injection, Solution | Vifor (International) Inc. | BLA |
| 59353-220 | Epoetin 10000 [iU]/mL Injection, Solution | Vifor (International) Inc. | BLA |
Frequently asked questions
What is Retacrit used for?
1 INDICATIONS AND USAGE RETACRIT is an erythropoiesis-stimulating agent (ESA) indicated for: • Treatment of anemia due to o Chronic Kidney Disease (CKD) in patients on dialysis and not on dialysis ( 1.1 ). o Zidovudine in patients with Human Immunodeficiency Virus (HIV) infection ( 1.2 ). o The effects of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two…
What are the side effects of Retacrit?
The following serious adverse reactions are discussed in greater detail in other sections of the label: • Increased Mortality, Myocardial Infarction, Stroke, and Thromboembolism [see Warnings and Precautions (5.1) ] • Increased mortality and/or increased risk of tumor progression or recurrence in Patients with Cancer [see Warnings and Precautions (5.2) ] • Hypertension [see Warnings and… See the full label for the complete list.
Who makes Retacrit?
Retacrit is listed by 2 labelers in the FDA NDC directory, including Pfizer Laboratories Div Pfizer Inc, Vifor (International) Inc..