RETACRIT™

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)].

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.

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Do not increase the dose more frequently than once every 4 weeks. Decreases in dose can occur more frequently. Avoid frequent dose adjustments.

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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.

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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%.

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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:

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Initiate RETACRIT treatment when the hemoglobin level is less than 10 g/dL.

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If the hemoglobin level approaches or exceeds 11 g/dL, reduce or interrupt the dose of RETACRIT.

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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:

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Consider initiating RETACRIT treatment only when the hemoglobin level is less than 10 g/dL and the following considerations apply:

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The rate of hemoglobin decline indicates the likelihood of requiring a RBC transfusion
and,

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Reducing the risk of alloimmunization and/or other RBC transfusion-related risks is a goal

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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.

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The recommended starting dose for adult patients is 50 to 100 Units/kg 3 times weekly intravenously or subcutaneously.

For pediatric patients with CKD:

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Initiate RETACRIT treatment only when the hemoglobin level is less than 10 g/dL.

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If the hemoglobin level approaches or exceeds 12 g/dL, reduce or interrupt the dose of RETACRIT.

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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).

Starting Dose

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

Dose Adjustment

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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.

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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.

Recommended Starting Dose

Dose Reduction

Reduce dose by 25% if:

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Hemoglobin increases greater than 1 g/dL in any 2-week period or

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Hemoglobin reaches a level needed to avoid RBC transfusion.

Withhold dose if hemoglobin exceeds a level needed to avoid RBC transfusion. Reinitiate at a dose 25% below the previous dose when hemoglobin approaches a level where RBC transfusions may be required.

Dose Increase

After the initial 4 weeks of RETACRIT therapy, if hemoglobin increases by less than 1 g/dL and remains below 10 g/dL, increase dose to:

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300 Units/kg three times per week in adults or

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60,000 Units weekly in adults

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900 Units/kg (maximum 60,000 Units) weekly in pediatric patients

After 8 weeks of therapy, if there is no response as measured by hemoglobin levels or if RBC transfusions are still required, discontinue RETACRIT.

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.

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.

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).

Patients with Chronic Kidney Disease

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:

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:

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:

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

Data

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.

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.

Adult Patients on Dialysis

Pediatric Patients with CKD on Dialysis

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

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

Adult Patients with CKD Not Requiring Dialysis

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

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

In TREAT, a randomized, double-blind trial of 4038 patients with CKD and type 2 diabetes not on dialysis, a post-hoc analysis showed that the proportion of patients receiving RBC transfusions was lower in patients administered an ESA to target a hemoglobin of 13 g/dL compared to the control arm in which an ESA was administered intermittently if hemoglobin concentration decreased to less than 9 g/dL (15% versus 25%, respectively). In CHOIR, a randomized open-label study of 1432 patients with CKD not on dialysis, use of epoetin alfa to target a higher (13.5 g/dL) versus lower (11.3 g/dL) hemoglobin goal did not reduce the use of RBC transfusions. In each trial, no benefits occurred for the cardiovascular or end-stage renal disease outcomes. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile [see Warnings and Precautions (5.1)].

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

Three randomized outcome trials (Normal Hematocrit Study [NHS], Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease [CHOIR], and Trial of Darbepoetin Alfa in Type 2 Diabetes and CKD [TREAT]) have been conducted in patients with CKD using epoetin alfa/darbepoetin alfa to target higher vs. lower hemoglobin levels. Though these trials were designed to establish a cardiovascular or renal benefit of targeting higher hemoglobin levels, in all 3 studies, patients randomized to the higher hemoglobin target experienced worse cardiovascular outcomes and showed no reduction in progression to ESRD. In each trial, the potential benefit of ESA therapy was offset by worse cardiovascular safety outcomes resulting in an unfavorable benefit-risk profile [see Warnings and Precautions (5.1)].

Study C1

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.

Study C2

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.

Pooled Analysis (Three Times Per Week Dosing)

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.