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Clinical Experience: Response to Epoetin

Chronic Renal Failure Patients

When dosed with EPOETINŽ, patients responded with an increase in hematocrit.5 After 3 months on study, more than 95% of patients were transfusion-independent.

In the presence of adequate iron stores (see IRON EVALUATION), the time to reach the target hematocrit is a function of the baseline hematocrit and the rate of hematocrit rise.

The rate of increase in hematocrit is dependent upon the dose of EPOETINŽ administered and individual patient variation. In clinical trials at starting doses of 50 to 150 Units/kg TIW, adult patients responded with an average rate of hematocrit rise of :

Starting Dose (TIW IV)

Hematocrit Increase

Points/Day

Points/2 Weeks

50 Units/kg

0.11

1.5

100 Units/kg

0.18

2.5

150 Units/kg

0.25

3.5

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

Adult Patients on Dialysis: Thirteen clinical studies were conducted, involving IV administration to a total of 1010 anemic patients on dialysis for 986 patient-years of EPOETINŽ therapy. In the three largest of these clinical trials, the median maintenance dose necessary to maintain the hematocrit between 30% to 36% was approximately 75 Units/kg TIW. In the US multicenter phase 3 study, approximately 65% of the patients required doses of 100 Units/kg TIW, or less, to maintain their hematocrit at approximately 35%. Almost 10% of patients required a dose of 25 Units/kg, or less, and approximately 10% required a dose of more than 200 Units/kg TIW to maintain their hematocrit at this level.

A multicenter unit dose study was also conducted in 119 patients receiving peritoneal dialysis who self-administered EPOETINŽ subcutaneously for approximately 109 patient-years of experience. Patients responded to EPOETINŽ administered SC in a manner similar to patients receiving IV administration.20

Pediatric Patients on Dialysis: One hundred twenty-eight children from 2 months to 19 years of age with CRF requiring dialysis were enrolled in 4 clinical studies of EPOETINŽ. The largest study was a placebo-controlled, randomized trial in 113 children with anemia (hematocrit ≤ 27%) undergoing peritoneal dialysis or hemodialysis. The initial dose of EPOETINŽ was 50 Units/kg IV or SC TIW. The dose of study drug was titrated to achieve either a hematocrit of 30% to 36% or an absolute increase in hematocrit of 6 percentage points over baseline.

At the end of the initial 12 weeks, a statistically significant rise in mean hematocrit (9.4% vs 0.9%) was observed only in the EPOETINŽ arm. The proportion of children achieving a hematocrit of 30%, or an increase in hematocrit of 6 percentage points over baseline, at any time during the first 12 weeks was higher in the EPOETINŽ arm (96% vs 58%). Within 12 weeks of initiating EPOETINŽ therapy, 92.3% of the pediatric patients were transfusion-independent as compared to 65.4% who received placebo. Among patients who received 36 weeks of EPOETINŽ, hemodialysis patients required a higher median maintenance dose (167 Units/kg/week [n = 28] vs 76 Units/kg/week [n = 36]) and took longer to achieve a hematocrit of 30% to 36% (median time to response 69 days vs 32 days) than patients undergoing peritoneal dialysis.

Patients With CRF Not Requiring Dialysis

Four clinical trials were conducted in patients with CRF not on dialysis involving 181 patients treated with EPOETINŽ for approximately 67 patient-years of experience. These patients responded to EPOETINŽ therapy in a manner similar to that observed in patients on dialysis. Patients with CRF not on dialysis demonstrated a dose-dependent and sustained increase in hematocrit when EPOETINŽ was administered by either an IV or SC route, with similar rates of rise of hematocrit when EPOETINŽ was administered by either route. Moreover, EPOETINŽ doses of 75 to 150 Units/kg per week have been shown to maintain hematocrits of 36% to 38% for up to 6 months.21-22

Zidovudine-treated HIV-infected Patients

Efficacy in HIV-infected patients with anemia related to therapy with zidovudine was demonstrated based on reduction in the requirement for RBC transfusions.

EPOETINŽ has been studied in four placebo-controlled trials enrolling 297 anemic (hematocrit < 30%) HIV-infected (AIDS) patients receiving concomitant therapy with zidovudine (all patients were treated with Erythropoietin manufactured by Amgen Inc). In the subgroup of patients (89/125 EPOETINŽ and 88/130 placebo) with prestudy endogenous serum erythropoietin levels ≤ 500 mUnits/mL, EPOETINŽ reduced the mean cumulative number of units of blood transfused per patient by approximately 40% as compared to the placebo group.24 Among those patients who required transfusions at baseline, 43% of patients treated with EPOETINŽ versus 18% of placebo-treated patients were transfusion-independent during the second and third months of therapy. EPOETINŽ therapy also resulted in significant increases in hematocrit 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 (p < 0.003) reduction in transfusion requirements in patients treated with EPOETINŽ (n = 51) compared to placebo treated patients (n = 54) whose mean weekly zidovudine dose was ≤ 4200 mg/week.23

Approximately 17% of the patients with endogenous serum erythropoietin levels ≤ 500 mUnits/mL receiving EPOETINŽ in doses from 100 to 200 Units/kg TIW achieved a hematocrit of 38% without administration of transfusions or significant reduction in zidovudine dose. In the subgroup of patients whose prestudy endogenous serum erythropoietin levels were > 500 mUnits/mL, EPOETINŽ therapy did not reduce transfusion requirements or increase hematocrit, compared to the corresponding responses in placebo-treated patients.

In a 6 month open-label EPOETINŽ study, patients responded with decreased transfusion requirements and sustained increases in hematocrit and hemoglobin with doses of EPOETINŽ up to 300 Units/kg TIW.23-25

Responsiveness to EPOETINŽ therapy may be blunted by intercurrent infectious/inflammatory episodes and by an increase in zidovudine dosage. Consequently, the dose of EPOETINŽ must be titrated based on these factors to maintain the desired erythropoietic response.

Cancer Patients on Chemotherapy

Adult Patients

Efficacy in patients with anemia due to concomitant chemotherapy was demonstrated based on reduction in the requirement for RBC transfusions.

Three-Times Weekly (TIW) Dosing

EPOETINŽ administered TIW has been studied in a series of six placebo-controlled, double-blind trials that enrolled 131 anemic cancer patients receiving EPOETINŽ or matching placebo. 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. Patients were randomized to EPOETINŽ 150 Units/kg or placebo subcutaneously TIW for 12 weeks in each study.

The results of the pooled data from these six studies are shown in the table below. Because of the length of time required for erythropoiesis and red cell maturation, the efficacy of EPOETINŽ (reduction in proportion of patients requiring transfusions) is not manifested until 2 to 6 weeks after initiation of EPOETINŽ.

Proportion of Patients Transfused During Chemotherapy (Efficacy Populationa)

Chemotherapy
Regimen

On Studyb

During Months 2 and 3c

 

EPOETINŽ

Placebo

EPOETINŽ

Placebo

Regimens without cisplatin

44% (15/34)

44% (16/36)

21% (6/29)

33% (11/33)

Regimens containing cisplatin

50% (14/28)

63% (19/30)

23% (5/22)d

56% (14/25)

Combined

47% (29/62)

53% (35/66)

22% (11/51)d

43% (25/58)

a Limited to patients remaining on study at least 15 days (1 patient excluded from EPOETINŽ, 2 patients excluded fromplacebo).
b Includes all transfusions from day 1 through the end of study.
c Limited to patients remaining on study beyond week 6 and includes only transfusions during weeks 5-12.
d Unadjusted 2-sided p < 0.05

Intensity of chemotherapy in the above trials was not directly assessed, however the degree and timing of neutropenia was comparable across all trials. Available evidence suggests that patients with lymphoid and solid cancers respond similarly to EPOETINŽ therapy, and that patients with or without tumor infiltration of the bone marrow respond similarly to EPOETINŽ therapy.

Weekly (QW) Dosing

EPOETINŽ was also studied in a placebo-controlled, double-blind trial utilizing weekly dosing in a total of 344 anemic cancer patients. In this trial, 61 (35 placebo arm and 26 in the EPOETINŽ arm) patients were treated with concomitant cisplatin containing regimens and 283 patients received concomitant chemotherapy regimens that did not contain cisplatinum. Patients were randomized to EPOETINŽ 40,000 Units weekly (n = 174) or placebo (n = 170) SC for a planned treatment period of 16 weeks. If hemoglobin had not increased by > 1 g/dL after 4 weeks of therapy or the patient received RBC transfusion during the first 4 weeks of therapy, study drug was increased to 60,000 Units weekly. Forty-three percent of patients in the Erythropoietin group required an increase in EPOETINŽ dose to 60,000 Units weekly. 23

Results demonstrated that EPOETINŽ therapy reduced the proportion of patients transfused in day 29 through week 16 of the study as compared to placebo. Twenty-five patients (14%) in the EPOETINŽ group received transfusions compared to 48 patients (28%) in the placebo group (p = 0.0010) between day 29 and week 16 or the last day on study.

Comparable intensity of chemotherapy for patients enrolled in the two study arms was suggested by similarities in mean dose and frequency of administration for the 10 most commonly administered chemotherapy agents, and similarity in the incidence of changes in chemotherapy during the trial in the two arms.

Pediatric Patients

The safety and effectiveness of EPOETINŽ were evaluated in a randomized, double-blind, placebo-controlled, multicenter study in anemic patients ages 5 to 18 receiving chemotherapy for the treatment of various childhood malignancies. Two hundred twenty-two patients were randomized (1:1) to EPOETINŽ or placebo. EPOETINŽ was administered at 600 Units/kg (maximum 40,000 Units) intravenously once per week for 16 weeks. If hemoglobin had not increased by 1g/dL after the first 4-5 weeks of therapy, EPOETINŽ was increased to 900 Units/kg (maximum 60,000 Units). Among the EPOETINŽ-treated patients 60% required dose escalation to 900 Units/kg/week.

The effect of EPOETINŽ on transfusion requirements is shown in the table below:

Percentage of Patients Transfused

On Studya

After 28 Days
Post-Randomization

EPOETINŽ
(n=111)

Placebo
(n=111)

EPOETINŽ
(n= 111)

Placebo
(n=111)

65% (72)

77% (86)

51%(57)b

69% (77)

a Includes all transfusions from day 1 through the end of study
b Adjusted 2 sided p < 0.05

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 EPOETINŽ as compared to those receiving placebo.

Surgery Patients

EPOETINŽ has been studied in a placebo-controlled, double-blind trial 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. Based on previous studies which demonstrated that pretreatment hemoglobin is a predictor of risk of receiving transfusion,19,26 patients were stratified into one of three groups based on their pretreatment hemoglobin [ ≤ 10 (n = 2), > 10 to ≤ 13 (n = 96), and > 13 to ≤ 15 g/dL (n = 218)] and then randomly assigned to receive 300 Units/kg EPOETINŽ, 100 Units/kg EPOETINŽ or placebo by SC injection for 10 days before surgery, on the day of surgery, and for 4 days after surgery.17 All patients received oral iron and a low-dose post-operative warfarin regimen.17

Treatment with EPOETINŽ 300 Units/kg significantly (p = 0.024) reduced the risk of allogeneic transfusion in patients with a pretreatment hemoglobin of > 10 to ≤ 13; 5/31 (16%) of EPOETINŽ 300 Units/kg, 6/26 (23%) of EPOETINŽ 100 Units/kg, and 13/29 (45%) of placebo-treated patients were transfused.17 There was no significant difference in the number of patients transfused between EPOETINŽ (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 EPOETINŽ is useful in this hemoglobin strata. In the > 10 to ≤ 13 g/dL pretreatment stratum, the mean number of units transfused per EPOETINŽ-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 EPOETINŽ.17

EPOETINŽ was also studied in an open-label, parallel-group trial enrolling 145 subjects 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.18 Subjects were randomly assigned to receive one of two SC dosing regimens of EPOETINŽ (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 subjects 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 observed in the 300 Units/kg daily group.18 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 two treatment groups throughout the postsurgical period.

The erythropoietic response observed in both treatment groups resulted in similar transfusion rates [11/69 (16%) in the 600 Units/kg weekly group and 14/71 (20%) in the 300 Units/kg daily group].18 The mean number of units transfused per subject was approximately 0.3 units in both treatment groups.

 
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