RETACRIT (Page 6 of 11)

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.

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)].

11 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).

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.

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.

14 CLINICAL STUDIES

14.1 Patients with Chronic Kidney Disease

Adult Patients on Dialysis

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

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

Table 8. Average Rate of Hemoglobin Rise in 2 Weeks
Starting Dose (3 Times Weekly Intravenously) Hemoglobin Increase in 2 Weeks

50 Units/kg

0.5 g/dL

100 Units/kg

0.8 g/dL

150 Units/kg

1.2 g/dL

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

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

Other ESA trials

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

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

Pediatric Patients with CKD on Dialysis

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

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

Adult Patients with CKD Not Requiring Dialysis

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

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

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

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

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

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