"The U.S. Food and Drug Administration is alerting health care providers and patients of a voluntary nationwide recall of all lots of Omontys Injection by Affymax, Inc., of Palo Alto, Calif., and Takeda Pharmaceuticals Company Limited, of Deerfiel"...
- Patient Information:
Details with Side Effects
Mechanism of Action
Epogen stimulates erythropoiesis by the same mechanism as endogenous erythropoietin.
Epogen increases 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 Epogen administered. For correction of anemia in hemodialysis patients, a greater biologic response is not observed at doses exceeding 300 Units/kg 3 times weekly.
In adult and pediatric patients with CKD, the elimination half-life (t½) of plasma erythropoietin after intravenous administration of Epogen ranged from 4 to 13 hours. After subcutaneous administration, Cmax was achieved within 5 to 24 hours. The t½ 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 Epogen t½ 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 t½ 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 Epogen in children and adolescents appeared similar to that of adults.
The pharmacokinetics of Epogen has not been studied in patients with HIV infection.
Reproductive and Developmental Toxicology
When pregnant rats were administered intravenous Epogen, 500 Units/kg/day, after the period of organogenesis (from day 17 of gestation through day 21 of lactation), their pups exhibited decreased number of caudal vertebrae, decreased body weight gain, and delayed appearance of abdominal hair, eyelid opening, and ossification. This animal dose level of 500 Units/kg/day is approximately 5-fold higher than the clinical recommended starting dose, depending on the patient's treatment indication.
When Epogen was administered intravenously during the period of organogenesis to pregnant rats (gestational days 7 to 17) and pregnant rabbits (gestational days 6 to 18), no evidence of teratogenic outcome was observed at the doses tested, up to 500 Units/kg/day. The offspring (F1 generation) of the treated rats were observed postnatally; rats from the F1 generation reached maturity and were mated; no Epogen-related effects were apparent for their offspring (F2 generation fetuses).
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 CKD patients on dialysis, Epogen increased hemoglobin levels and decreased the need for RBC transfusion. Overall, more than 95% of patients were RBC transfusion-independent after receiving Epogen 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 Epogen were evaluated in 13 clinical studies involving intravenous administration to a total of 1010 anemic patients on dialysis. Overall, more than 90% of the patients treated with Epogen 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 Epogen or placebo. By the end of the study, average hemoglobin increased to approximately 11 g/dL in the Epogen-treated patients and remained unchanged in patients receiving placebo. Epogen-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 Epogen subcutaneously. Patients responded to Epogen administered subcutaneously in a manner similar to patients receiving intravenous administration.
Pediatric Patients on Dialysis
The safety and efficacy of Epogen were studied in a placebo-controlled, randomized study of 113 children with anemia (hemoglobin ≤ 9 g/dL) undergoing peritoneal dialysis or hemodialysis. The initial dose of Epogen 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 Epogen arm. The proportion of children 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 Epogen arm (96% vs. 58%). Within 12 weeks of initiating Epogen 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 Epogen, 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 Epogen. These patients responded to Epogen 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 Epogen was administered by either an intravenous or subcutaneous route, with similar rates of rise of hemoglobin when Epogen 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].
ESA Effects on rates of death and other serious cardiac adverse events
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 Epogen/PROCRIT/Aranesp 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].
Zidovudine-treated Patients With HIV Infection
The safety and efficacy of Epogen were evaluated in 4 placebo-controlled studies enrolling 297 anemic patients (hemoglobin < 10 g/dL) with HIV infection receiving concomitant therapy with zidovudine. In the subgroup of patients (89/125 Epogen and 88/130 placebo) with pre-study endogenous serum erythropoietin levels ≤ 500 mUnits/mL, Epogen reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group. Among those patients who required RBC transfusions at baseline, 43% of patients treated with Epogen versus 18% of placebo-treated patients were RBC transfusion-independent during the second and third months of therapy. Epogen therapy also resulted in significant increases in hemoglobin in comparison to placebo. When examining the results according to the weekly dose of zidovudine received during month 3 of therapy, there was a statistically significant reduction (p < 0.003) in RBC transfusion requirements in patients treated with Epogen (n = 51) compared to placebo-treated patients (n = 54) whose mean weekly zidovudine dose was ≤ 4200 mg/week.
Approximately 17% of the patients with endogenous serum erythropoietin levels ≤ 500 mUnits/mL receiving Epogen in doses from 100 to 200 Units/kg 3 times weekly achieved a hemoglobin of 12.7 g/dL without administration of RBC transfusions or significant reduction in zidovudine dose. In the subgroup of patients whose pre-study endogenous serum erythropoietin levels were > 500 mUnits/mL, Epogen therapy did not reduce RBC transfusion requirements or increase hemoglobin compared to the corresponding responses in placebo-treated patients.
Cancer Patients on Chemotherapy
The safety and effectiveness of Epogen was assessed in two multicenter, randomized (1:1), placebo-controlled, double-blind studies (Study C1 and Study C2) and a pooled analysis of six additional randomized (1:1), multicenter, placebo-controlled, double-blind studies. All studies were conducted in patients with anemia due to concomitantly administered cancer chemotherapy. Study C1 enrolled 344 adult patients, Study C2 enrolled 222 pediatric patients, and the pooled analysis contained 131 patients randomized to epoetin alfa or placebo. In Studies C1 and C2, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion, from week 5 through end of the study, with the last-known RBC transfusion status carried forward for patients who discontinued treatment. In the pooled analysis, efficacy was demonstrated by a reduction in the proportion of patients who received an RBC transfusion from week 5 through end of the study in the subset of patients who were remaining on therapy for 6 or more weeks.
Study C1 was conducted in anemic patients (hemoglobin < 11.5 g/dL for males; < 10.5 g/dL for females) with non-myeloid malignancies receiving myelosuppressive chemotherapy. Randomization was stratified by type of malignancy (lung vs. breast vs. other), concurrent radiation therapy planned (yes or no), and baseline hemoglobin ( < 9 g/dL vs. ≥ 9 g/dL); patients were randomized to epoetin alfa 40,000 Units (n = 174) or placebo (n = 170) as a weekly subcutaneous injection commencing on the first day of the chemotherapy cycle.
Ninety-one percent of patients were white, 44% were male, and the median age of patients was 66 years (range: 20 to 88 years). The proportion of patients withdrawn from the study prior to week 5 was less than 10% for placebo-treated or epoetin-treated patients. Per protocol, the last available hemoglobin values from patients who dropped out were included in the efficacy analyses. Efficacy results are shown in Table 9.
Table 9: Study C1: Proportion of Patients Transfused
|Chemotherapy Regimen||Week 5 Through Week 16 or End of Studyb|
(n = 174)
(n = 170)
|All Regimens||14% (25/174)a||28% (48/170)|
|Regimens without cisplatin||14% (21/148)||26% (35/137)|
|Regimens containing cisplatin||15% (4/26)||39% (13/33)|
|aTwo-sided p < 0.001, logistic
regression analysis adjusting for accrual rate and stratification variables
b Last-known RBC transfusion status carried forward for patients who discontinued treatment.
Study C2 was conducted in 222 anemic patients, 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 Epogen 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.
Table 10: Proportion of Patients Transfused in the Pooled
Analysis for Three Times Per Week Dosing
|Chemotherapy Regimen||Week 5 Through Week 12 or End of Studyb|
|All Regimens||22% (11/51)a||43% (25/58)|
|Regimens without cisplatin||21% (6/29)||33% (11/33)|
|Regimens containing cisplatin||23% (5/22)||56% (14/25)|
|aTwo-sided p < 0.05, unadjusted
b Limited to patients remaining on study beyond week 6 and includes only RBC transfusions during weeks 5-12.
The safety and efficacy of Epogen were evaluated in a placebo-controlled, double-blind study (S1) enrolling 316 patients scheduled for major, elective orthopedic hip or knee surgery who were expected to require ≥ 2 units of blood and who were not able or willing to participate in an autologous blood donation program. Patients were stratified into 1 of 3 groups based on their pretreatment hemoglobin [ ≤ 10 g/dL (n = 2), > 10 to ≤ 13 g/dL (n = 96), and > 13 to ≤ 15 g/dL (n = 218)] and then randomly assigned to receive 300 Units/kg Epogen, 100 Units/kg Epogen, or placebo by subcutaneous injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery. All patients received oral iron and a low-dose, postoperative warfarin regimen.
Treatment with Epogen 300 Units/kg significantly (p = 0.024) reduced the risk of allogeneic RBC transfusion in patients with a pretreatment hemoglobin of > 10 to ≤ 13 g/dL; 5/31 (16%) of patients treated with Epogen 300 Units/kg, 6/26 (23%) of patients treated with Epogen 100 Units/kg, and 13/29 (45%) of placebo-treated patients were transfused. There was no significant difference in the number of patients transfused between Epogen (9% 300 Units/kg, 6% 100 Units/kg) and placebo (13%) in the > 13 to ≤ 15 g/dL hemoglobin stratum. There were too few patients in the ≤ 10 g/dL group to determine if Epogen is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per Epogen-treated patient (0.45 units blood for 300 Units/kg, 0.42 units blood for 100 Units/kg) was less than the mean transfused per placebo-treated patient (1.14 units) (overall p = 0.028). In addition, mean hemoglobin, hematocrit, and reticulocyte counts increased significantly during the presurgery period in patients treated with Epogen.
Epogen was also evaluated in an open-label, parallel-group study (S2) enrolling 145 patients with a pretreatment hemoglobin level of ≥ 10 to ≤ 13 g/dL who were scheduled for major orthopedic hip or knee surgery and who were not participating in an autologous program. Patients were randomly assigned to receive 1 of 2 subcutaneous dosing regimens of Epogen (600 Units/kg once weekly for 3 weeks prior to surgery and on the day of surgery, or 300 Units/kg once daily for 10 days prior to surgery, on the day of surgery, and for 4 days after surgery). All patients received oral iron and appropriate pharmacologic anticoagulation therapy.
From pretreatment to presurgery, the mean increase in hemoglobin in the 600 Units/kg weekly group (1.44 g/dL) was greater than that observed in the 300 Units/kg daily group. The mean increase in absolute reticulocyte count was smaller in the weekly group (0.11 x 106/mm³) compared to the daily group (0.17 x 106/mm³). Mean hemoglobin levels were similar for the 2 treatment groups throughout the postsurgical period.
The erythropoietic response observed in both treatment groups resulted in similar RBC transfusion rates [11/69 (16%) in the 600 Units/kg weekly group and 14/71 (20%) in the 300 Units/kg daily group]. The mean number of units transfused per patient was approximately 0.3 units in both treatment groups.
Last reviewed on RxList: 6/20/2012
This monograph has been modified to include the generic and brand name in many instances.
Additional Epogen Information
Epogen - User Reviews
Epogen User Reviews
Now you can gain knowledge and insight about a drug treatment with Patient Discussions.
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
Find out what women really need.