RETACRIT
These highlights do not include all the information needed to use RETACRIT safely and effectively. See full prescribing information for RETACRIT. RETACRIT (epoetin alfa-epbx) injection, for intravenous or subcutaneous use Initial U.S. Approval: 2018 RETACRIT (epoetin alfa-epbx) is biosimilar to EPOGEN/PROCRIT (epoetin alfa)
3af26b0d-8ad0-44e1-a538-8bdb5ab39374
HUMAN PRESCRIPTION DRUG LABEL
Jun 8, 2023
Pfizer Laboratories Div Pfizer Inc
DUNS: 134489525
Products 7
Detailed information about drug products covered under this FDA approval, including NDC codes, dosage forms, ingredients, and administration routes.
epoetin alfa-epbx
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epoetin alfa-epbx
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epoetin alfa-epbx
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epoetin alfa-epbx
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epoetin alfa-epbx
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epoetin alfa-epbx
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Drug Labeling Information
INDICATIONS & USAGE SECTION
1 INDICATIONS AND USAGE
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.
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 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 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).
WARNINGS AND PRECAUTIONS SECTION
5 WARNINGS AND PRECAUTIONS
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) |
CHOIR |
TREAT | |
---|---|---|---|
Time Period of Trial |
1993 to 1996 |
2003 to 2006 |
2004 to 2009 |
Population |
CKD patients on hemodialysis with coexisting CHF or CAD, hematocrit 30 ± 3% on epoetin alfa |
CKD patients not on dialysis with hemoglobin < 11 g/dL not previously administered epoetin alfa |
CKD patients not on dialysis with type II diabetes, hemoglobin ≤ 11 g/dL |
Hemoglobin Target; Higher vs. Lower (g/dL) |
14.0 vs. 10.0 |
13.5 vs. 11.3 |
13.0 vs. ≥ 9.0 |
Median (Q1, Q3) Achieved Hemoglobin level (g/dL) |
12.6 (11.6, 13.3) vs. 10.3 (10.0, 10.7) |
13.0 (12.2, 13.4) vs. 11.4 (11.1, 11.6) |
12.5 (12.0, 12.8) vs. 10.6 (9.9, 11.3) |
Primary Endpoint |
All-cause mortality or non-fatal MI |
All-cause mortality, MI, hospitalization for CHF, or stroke |
All-cause mortality, MI, myocardial ischemia, heart failure, and stroke |
Hazard Ratio or Relative Risk (95% CI) |
1.28 (1.06 – 1.56) |
1.34 (1.03 – 1.74) |
1.05 (0.94 – 1.17) |
Adverse Outcome for Higher Target Group |
All-cause mortality |
All-cause mortality |
Stroke |
Hazard Ratio or Relative Risk (95% CI) |
1.27 (1.04 – 1.54) |
1.48 (0.97 – 2.27) |
1.92 (1.38 – 2.68) |
Patients with Chronic Kidney Disease
Normal Hematocrit Study (NHS): A prospective, randomized, open-label study of 1265 patients with chronic kidney disease on dialysis with documented evidence of congestive heart failure or ischemic heart disease was designed to test the hypothesis that a higher target hematocrit (Hct) would result in improved outcomes compared with a lower target Hct. In this study, patients were randomized to epoetin alfa treatment targeted to a maintenance hemoglobin of either 14 ± 1 g/dL or 10 ± 1 g/dL. The trial was terminated early with adverse safety findings of higher mortality in the high hematocrit target group. Higher mortality (35% vs. 29%) was observed for the patients randomized to a target hemoglobin of 14 g/dL than for the patients randomized to a target hemoglobin of 10 g/dL. For all-cause mortality, the HR = 1.27; 95% CI (1.04, 1.54); p = 0.018. The incidence of nonfatal myocardial infarction, vascular access thrombosis, and other thrombotic events was also higher in the group randomized to a target hemoglobin of 14 g/dL.
CHOIR: A randomized, prospective trial, 1432 patients with anemia due to CKD who were not undergoing dialysis and who had not previously received epoetin alfa therapy were randomized to epoetin alfa treatment targeting a maintenance hemoglobin concentration of either 13.5 g/dL or 11.3 g/dL. The trial was terminated early with adverse safety findings. A major cardiovascular event (death, myocardial infarction, stroke, or hospitalization for congestive heart failure) occurred in 125 of the 715 patients (18%) in the higher hemoglobin group compared to 97 of the 717 patients (14%) in the lower hemoglobin group [hazard ratio (HR) 1.34, 95% CI: 1.03, 1.74; p=0.03].
TREAT: A randomized, double-blind, placebo-controlled, prospective trial of 4038 patients with: CKD not on dialysis (eGFR of 20 – 60 mL/min), anemia (hemoglobin levels ≤ 11 g/dL), and type 2 diabetes mellitus, patients were randomized to receive either darbepoetin alfa treatment or a matching placebo. Placebo group patients also received darbepoetin alfa when their hemoglobin levels were below 9 g/dL. The trial objectives were to demonstrate the benefit of darbepoetin alfa treatment of the anemia to a target hemoglobin level of 13 g/dL, when compared to a "placebo" group, by reducing the occurrence of either of two primary endpoints: (1) a composite cardiovascular endpoint of all-cause mortality or a specified cardiovascular event (myocardial ischemia, CHF, MI, and CVA) or (2) a composite renal endpoint of all-cause mortality or progression to end stage renal disease. The overall risks for each of the two primary endpoints (the cardiovascular composite and the renal composite) were not reduced with darbepoetin alfa treatment (see Table 1), but the risk of stroke was increased nearly two-fold in the darbepoetin alfa-treated group versus the placebo group: annualized stroke rate 2.1% vs. 1.1%, respectively, HR 1.92; 95% CI: 1.38, 2.68; p < 0.001. The relative risk of stroke was particularly high in patients with a prior stroke: annualized stroke rate 5.2% in the darbepoetin alfa-treated group and 1.9% in the placebo group, HR 3.07; 95% CI: 1.44, 6.54. Also, among darbepoetin alfa-treated subjects with a past history of cancer, there were more deaths due to all causes and more deaths adjudicated as due to cancer, in comparison with the control group.
Patients with Cancer
An increased incidence of thromboembolic reactions, some serious and life- threatening, occurred in patients with cancer treated with ESAs.
In a randomized, placebo-controlled study (Study 2 in Table 2 [see Warnings and Precautions (5.2)]) of 939 women with metastatic breast cancer receiving chemotherapy, patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered to prevent anemia (maintain hemoglobin levels between 12 and 14 g/dL or hematocrit between 36% and 42%). This study was terminated prematurely when interim results demonstrated a higher mortality at 4 months (8.7% vs. 3.4%) and a higher rate of fatal thrombotic reactions (1.1% vs. 0.2%) in the first 4 months of the study among patients treated with epoetin alfa. Based on Kaplan-Meier estimates, at the time of study termination, the 12-month survival was lower in the epoetin alfa group than in the placebo group (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
Patients Having Surgery
An increased incidence of deep venous thrombosis (DVT) in patients receiving epoetin alfa undergoing surgical orthopedic procedures was demonstrated [see Adverse Reactions (6.1)]. In a randomized, controlled study, 680 adult patients, not receiving prophylactic anticoagulation and undergoing spinal surgery, were randomized to 4 doses of 600 Units/kg epoetin alfa (7, 14, and 21 days before surgery, and the day of surgery) and standard of care (SOC) treatment (n = 340) or to SOC treatment alone (n = 340). A higher incidence of DVTs, determined by either color flow duplex imaging or by clinical symptoms, was observed in the epoetin alfa group (16 [4.7%] patients) compared with the SOC group (7 [2.1%] patients). In addition to the 23 patients with DVTs included in the primary analysis, 19 [2.8%] patients (n = 680) experienced 1 other thrombovascular event (TVE) each (12 [3.5%] in the epoetin alfa group and 7 [2.1%] in the SOC group). Deep venous thrombosis prophylaxis is strongly recommended when ESAs are used for the reduction of allogeneic RBC transfusions in surgical patients [see Dosage and Administration (2.5)].
Increased mortality was observed in a randomized, placebo-controlled study of epoetin alfa in adult patients who were undergoing CABG surgery (7 deaths in 126 patients randomized to epoetin alfa versus no deaths among 56 patients receiving placebo). Four of these deaths occurred during the period of study drug administration and all 4 deaths were associated with thrombotic events.
5.2 Increased Mortality and/or Increased Risk of Tumor Progression or
Recurrence in Patients with Cancer
ESAs resulted in decreased locoregional control/progression-free survival (PFS) and/or overall survival (OS) (see Table 2).
Adverse effects on PFS and/or OS were observed in studies of patients receiving chemotherapy for breast cancer (Studies 1, 2, and 4), lymphoid malignancy (Study 3), and cervical cancer (Study 5); in patients with advanced head and neck cancer receiving radiation therapy (Studies 6 and 7); and in patients with non-small cell lung cancer or various malignancies who were not receiving chemotherapy or radiotherapy (Studies 8 and 9).
Table 2. Randomized, Controlled Studies with Decreased Survival and/or Decreased Locoregional Control
Study/Tumor/(n) |
Hemoglobin Target |
Achieved Hemoglobin (Median; Q1, Q3***)** |
Primary Efficacy Outcome |
Adverse Outcome for ESA-containing Arm |
---|---|---|---|---|
†
| ||||
Chemotherapy | ||||
Study 1 |
≤12 g/dL† |
11.6 g/dL; |
Progression-free survival (PFS) |
Decreased progression-free and overall survival |
Study 2 |
12–14 g/dL |
12.9 g/dL; |
12-month overall survival |
Decreased 12-month survival |
Study 3 |
13–15 g/dL (M) |
11 g/dL; |
Proportion of patients achieving a hemoglobin response |
Decreased overall survival |
Study 4 |
12.5–13 g/dL |
13.1 g/dL; |
Relapse-free and overall survival |
Decreased 3-year relapse-free and overall survival |
Study 5 |
12–14 g/dL |
12.7 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 |
≥ 15 g/dL (M) |
Not available |
Locoregional progression-free survival |
Decreased 5-year locoregional progression-free and overall survival |
Study 7 |
14–15.5 g/dL |
Not available |
Locoregional disease control |
Decreased locoregional disease control |
No Chemotherapy or Radiotherapy | ||||
Study 8 |
12–14 g/dL |
Not available |
Quality of life |
Decreased overall survival |
Study 9 |
12–13 g/dL |
10.6 g/dL; |
RBC transfusions |
Decreased overall survival |
Decreased Overall Survival
Study 2 was described in the previous section [see Warnings and Precautions (5.1)]. Mortality at 4 months (8.7% vs. 3.4%) was significantly higher in the epoetin alfa arm. The most common investigator-attributed cause of death within the first 4 months was disease progression; 28 of 41 deaths in the epoetin alfa arm and 13 of 16 deaths in the placebo arm were attributed to disease progression. Investigator-assessed time to tumor progression was not different between the 2 groups. Survival at 12 months was significantly lower in the epoetin alfa arm (70% vs. 76%; HR 1.37, 95% CI: 1.07, 1.75; p = 0.012).
Study 3 was a randomized, double-blind study (darbepoetin alfa vs. placebo) conducted in 344 anemic patients with lymphoid malignancy receiving chemotherapy. With a median follow-up of 29 months, overall mortality rates were significantly higher among patients randomized to darbepoetin alfa as compared to placebo (HR 1.36, 95% CI: 1.02, 1.82).
Study 8 was a multicenter, randomized, double-blind study (epoetin alfa vs. placebo) in which patients with advanced non-small cell lung cancer receiving only palliative radiotherapy or no active therapy were treated with epoetin alfa to achieve and maintain hemoglobin levels between 12 and 14 g/dL. Following an interim analysis of 70 patients (planned accrual 300 patients), a significant difference in survival in favor of the patients in the placebo arm of the study was observed (median survival 63 vs. 129 days; HR 1.84; p = 0.04).
Study 9 was a randomized, double-blind study (darbepoetin alfa vs. placebo) in 989 anemic patients with active malignant disease, neither receiving nor planning to receive chemotherapy or radiation therapy. There was no evidence of a statistically significant reduction in proportion of patients receiving RBC transfusions. The median survival was shorter in the darbepoetin alfa treatment group than in the placebo group (8 months vs. 10.8 months; HR 1.30, 95% CI: 1.07, 1.57).
Decreased Progression-free Survival and Overall Survival
Study 1 was a randomized, open-label, multicenter study in 2,098 anemic women with metastatic breast cancer, who received first line or second line chemotherapy. This was a non-inferiority study designed to rule out a 15% risk increase in tumor progression or death of epoetin alfa plus standard of care (SOC) as compared with SOC alone. At the time of clinical data cutoff, the median progression free survival (PFS) per investigator assessment of disease progression was 7.4 months in each arm (HR 1.09, 95% CI: 0.99, 1.20), indicating the study objective was not met. There were more deaths from disease progression in the epoetin alfa plus SOC arm (59% vs. 56%) and more thrombotic vascular events in the epoetin alfa plus SOC arm (3% vs. 1%). At the final analysis, 1653 deaths were reported (79.8% subjects in the epoetin alfa plus SOC group and 77.8% subjects in the SOC group). Median overall survival in the epoetin alfa plus SOC group was 17.8 months compared with 18.0 months in the SOC alone group (HR 1.07, 95% CI: 0.97, 1.18).
Study 4 was a randomized, open-label, controlled, factorial design study in which darbepoetin alfa was administered to prevent anemia in 733 women receiving neo-adjuvant breast cancer treatment. A final analysis was performed after a median follow-up of approximately 3 years. The 3-year survival rate was lower (86% vs. 90%; HR 1.42, 95% CI: 0.93, 2.18) and the 3-year relapse- free survival rate was lower (72% vs. 78%; HR 1.33, 95% CI: 0.99, 1.79) in the darbepoetin alfa-treated arm compared to the control arm.
Study 5 was a randomized, open-label, controlled study that enrolled 114 of a planned 460 cervical cancer patients receiving chemotherapy and radiotherapy. Patients were randomized to receive epoetin alfa to maintain hemoglobin between 12 and 14 g/dL or to RBC transfusion support as needed. The study was terminated prematurely due to an increase in thromboembolic adverse reactions in epoetin alfa-treated patients compared to control (19% vs. 9%). Both local recurrence (21% vs. 20%) and distant recurrence (12% vs. 7%) were more frequent in epoetin alfa-treated patients compared to control. Progression- free survival at 3 years was lower in the epoetin alfa-treated group compared to control (59% vs. 62%; HR 1.06, 95% CI: 0.58, 1.91). Overall survival at 3 years was lower in the epoetin alfa-treated group compared to control (61% vs. 71%; HR 1.28, 95% CI: 0.68, 2.42).
Study 6 was a randomized, placebo-controlled study in 351 head and neck cancer patients where epoetin beta or placebo was administered to achieve target hemoglobins ≥ 14 and ≥ 15 g/dL for women and men, respectively. Locoregional progression-free survival was significantly shorter in patients receiving epoetin beta (HR 1.62, 95% CI: 1.22, 2.14; p = 0.0008) with medians of 406 days and 745 days in the epoetin beta and placebo arms, respectively. Overall survival was significantly shorter in patients receiving epoetin beta (HR 1.39, 95% CI: 1.05, 1.84; p = 0.02).
Decreased Locoregional Control
Study 7 was a randomized, open-label, controlled study conducted in 522 patients with primary squamous cell carcinoma of the head and neck receiving radiation therapy alone (no chemotherapy) who were randomized to receive darbepoetin alfa to maintain hemoglobin levels of 14 to 15.5 g/dL or no darbepoetin alfa. An interim analysis performed on 484 patients demonstrated that locoregional control at 5 years was significantly shorter in patients receiving darbepoetin alfa (RR 1.44, 95% CI: 1.06, 1.96; p = 0.02). Overall survival was shorter in patients receiving darbepoetin alfa (RR 1.28, 95% CI: 0.98, 1.68; p = 0.08).
5.3 Hypertension
RETACRIT is contraindicated in patients with uncontrolled hypertension. Following initiation and titration of epoetin alfa, approximately 25% of patients on dialysis required initiation of or increases in antihypertensive therapy; hypertensive encephalopathy and seizures have been reported in patients with CKD receiving epoetin alfa.
Appropriately control hypertension prior to initiation of and during treatment with RETACRIT. Reduce or withhold RETACRIT if blood pressure becomes difficult to control. Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions [see Patient Counseling Information (17)].
5.4 Seizures
Epoetin alfa products, including RETACRIT, increase the risk of seizures in patients with CKD. During the first several months following initiation of RETACRIT, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for new-onset seizures, premonitory symptoms or change in seizure frequency.
5.5 Lack or Loss of Hemoglobin Response to RETACRIT
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 Warnings and Precautions (5.6)]. In the absence of PRCA, follow dosing recommendations for management of patients with an insufficient hemoglobin response to RETACRIT therapy [see Dosage and Administration (2.2)].
5.6 Pure Red Cell Aplasia
Cases of PRCA and of severe anemia, with or without other cytopenias that arise following the development of neutralizing antibodies to erythropoietin have been reported in patients treated with epoetin alfa. This has been reported predominantly in patients with CKD receiving ESAs by subcutaneous administration. PRCA has also been reported in patients receiving ESAs for anemia related to hepatitis C treatment (an indication for which RETACRIT is not approved).
If severe anemia and low reticulocyte count develop during treatment with RETACRIT, withhold RETACRIT and evaluate patients for neutralizing antibodies to erythropoietin. Contact Hospira, Inc., a Pfizer Company (1-800-438-1985) to perform assays for binding and neutralizing antibodies. Permanently discontinue RETACRIT in patients who develop PRCA following treatment with RETACRIT or other erythropoietin protein drugs. Do not switch patients to other ESAs.
5.7 Serious Allergic Reactions
Serious allergic reactions, including anaphylactic reactions, angioedema, bronchospasm, skin rash, and urticaria may occur with epoetin alfa products. Immediately and permanently discontinue RETACRIT and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs.
5.8 Severe Cutaneous Reactions
Blistering and skin exfoliation reactions including Erythema multiforme and Stevens-Johnson Syndrome (SJS)/Toxic Epidermal Necrolysis (TEN), have been reported in patients treated with ESAs (including epoetin alfa) in the postmarketing setting. Discontinue RETACRIT therapy immediately if a severe cutaneous reaction, such as SJS/TEN, is suspected.
5.9 Risk of Serious Adverse Reactions Due to Benzyl Alcohol Preservative
RETACRIT from multiple-dose vials contains benzyl alcohol and is contraindicated for use in neonates, infants, pregnant women, and lactating women [see Contraindications (4)]. In addition, do not mix RETACRIT with bacteriostatic saline (which also contains benzyl alcohol) when administering RETACRIT to these patient populations [see Dosage and Administration (2)].
Serious and fatal reactions including "gasping syndrome" can occur in neonates and infants treated with benzyl alcohol-preserved drugs, including RETACRIT multiple-dose vials. The "gasping syndrome" is characterized by central nervous system depression, metabolic acidosis, and gasping respirations. There is a potential for similar risks to fetuses and infants exposed to benzyl alcohol in utero or in breast-fed milk, respectively. RETACRIT multiple-dose vials contain 8.5 mg of benzyl alcohol per mL. The minimum amount of benzyl alcohol at which serious adverse reactions may occur is not known [see Use in Specific Populations (8.1,8.2, and 8.4)].
5.10 Risks in Patients with Phenylketonuria
Phenylalanine can be harmful to patients with phenylketonuria (PKU). RETACRIT contains phenylalanine, a component of aspartame. Each 1 mL single-dose vial of 2,000, 3,000, 4,000, 10,000, and 40,000 Units of epoetin alfa-epbx injection contains 0.5 mg of phenylalanine. Before prescribing RETACRIT to a patient with PKU, consider the combined daily amount of phenylalanine from all sources, including RETACRIT.
5.11 Dialysis Management
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.
•
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).
ADVERSE REACTIONS SECTION
6 ADVERSE REACTIONS
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)]
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 |
Placebo-treated Patients |
---|---|---|
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 |
Placebo-treated Patients |
---|---|---|
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. Adverse Reactions in Zidovudine-treated Patients with HIV- infection
Adverse Reaction |
Epoetin alfa |
Placebo |
---|---|---|
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 |
Patients with Cancer on Chemotherapy
The data below were obtained in Study C1, a 16-week, double-blind, placebo- controlled study that enrolled 344 patients with anemia secondary to chemotherapy. There were 333 patients who were evaluable for safety; 168 of 174 patients (97%) randomized to 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 |
Placebo |
---|---|---|
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% |
Surgery Patients
Four hundred sixty-one patients undergoing major orthopedic surgery were studied in a placebo-controlled study (S1) and a comparative dosing study (2 dosing regimens, S2). A total of 358 patients were randomly assigned to receive 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 |
Epoetin alfa |
Placebo |
Epoetin alfa |
Epoetin alfa | |
(n = 112)* |
(n = 101)* |
(n = 103)* |
(n = 73)† |
(n = 72)† | |
| |||||
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%‡ |
0%‡ |
Cough |
5% |
4% |
0% |
4% |
4% |
Hypertension |
5% |
3% |
5% |
5% |
6% |
Rash |
2% |
2% |
1% |
3% |
3% |
Edema |
1% |
2% |
2% |
1% |
3% |
6.2 Postmarketing Experience
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.
•
Seizures [see Warnings and Precautions (5.4)]
•
PRCA [see Warnings and Precautions (5.6)]
•
Serious allergic reactions [see Warnings and Precautions (5.7)]
•
Injection site reactions, including irritation and pain
•
Porphyria
•
Severe Cutaneous Reactions [see Warnings and Precautions (5.8)]
6.3 Immunogenicity
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 in the studies described below with the incidence of antibodies to other epoetin alfa 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 (5.6)].
•
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.
CLINICAL PHARMACOLOGY SECTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
Epoetin alfa products stimulate erythropoiesis by the same mechanism as endogenous erythropoietin.
12.2 Pharmacodynamics
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.
12.3 Pharmacokinetics
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.
NONCLINICAL TOXICOLOGY SECTION
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
HOW SUPPLIED SECTION
16 HOW SUPPLIED/STORAGE AND HANDLING
RETACRIT (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 0069-1305-10 |
2,000 Units/mL |
NDC 0069-1305-01 |
NDC 0069-1306-10 |
3,000 Units/mL |
NDC 0069-1306-01 |
NDC 0069-1307-10 |
4,000 Units/mL |
NDC 0069-1307-01 |
NDC 0069-1308-10 |
10,000 Units/mL |
NDC 0069-1308-01 |
NDC 0069-1309-10 |
40,000 Units/mL |
NDC 0069-1309-01 |
NDC 0069-1309-04 |
40,000 Units/mL |
NDC 0069-1309-01 |
NDC 0069-1318-10 |
20,000 Units/2 mL |
NDC 0069-1318-01 |
NDC 0069-1318-04 |
20,000 Units/2 mL |
NDC 0069-1318-01 |
NDC 0069-1311-10 |
20,000 Units/mL |
NDC 0069-1311-01 |
NDC 0069-1311-04 |
20,000 Units/mL |
NDC 0069-1311-01 |
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.